Journal articles on the topic 'K-ras cancer cells'
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1
Hamada, Shin, Ryotaro Matsumoto, Yu Tanaka, Keiko Taguchi, Masayuki Yamamoto, and Atsushi Masamune. "Nrf2 Activation Sensitizes K-Ras Mutant Pancreatic Cancer Cells to Glutaminase Inhibition." International Journal of Molecular Sciences 22, no. 4 (February 14, 2021): 1870. http://dx.doi.org/10.3390/ijms22041870.
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Pancreatic cancer remains intractable owing to the lack of effective therapy for unresectable cases. Activating mutations of K-ras are frequently found in pancreatic cancers, but these have not yet been targeted by cancer therapies. The Keap1-Nrf2 system plays a crucial role in mediating the oxidative stress response, which also contributes to cancer progression. Nrf2 activation reprograms the metabolic profile to promote the proliferation of cancer cells. A recent report suggested that K-ras- and Nrf2-active lung cancer cells are sensitive to glutamine depletion. This finding led to the recognition of glutaminase inhibitors as novel anticancer agents. In the current study, we used murine pancreatic cancer tissues driven by mutant K-ras and p53 to establish cell lines expressing constitutively activated Nrf2. Genetic or pharmacological Nrf2 activation in cells via Keap1 deletion or Nrf2 activation sensitized cells to glutaminase inhibition. This phenomenon was confirmed to be dependent on K-ras activation in human pancreatic cancer cell lines harboring mutant K-ras, i.e., Panc-1 and MiaPaCa-2 in response to DEM pretreatment. This phenomenon was not observed in BxPC3 cells harboring wildtype K-ras. These results indicate the possibility of employing Nrf2 activation and glutaminase inhibition as novel therapeutic interventions for K-ras mutant pancreatic cancers.
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Tan, Guang, Xin Zhang, Hongbo Feng, Haifeng Luo, and Zhongyu Wang. "The Therapeutic Effect of Cytokine-Induced Killer Cells on Pancreatic Cancer Enhanced by Dendritic Cells Pulsed with K-Ras Mutant Peptide." Clinical and Developmental Immunology 2011 (2011): 1–9. http://dx.doi.org/10.1155/2011/649359.
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Objective. This study is to investigate the role of the CIKs cocultured with K-ras-DCs in killing of pancreatic cancer cell lines, PANC-1 (K-ras+) and SW1990 (K-ras−).Methods. CIKs induced by IFN-γ, IL-2, and anti-CD3 monoantibody, K-ras-DCCIKs obtained by cocultivation of k-ras-DCs and CIKs. Surface markers examined by FACS. IFN-γIL-12 ,CCL19 and CCL22 detected by ELISA. Proliferation of various CIKs tested via 3H-TdR. Killing activities of k-ras-DCCIKs and CTLs examined with 125IUdR.Results. CD3+CD56+and CD3+CD8+were highly expressed by K-ras-DCCIKs. In its supernatant, IFN-γ, IL-12, CCL19 and CCL22 were significantly higher than those in DCCIK and CIK. The killing rate of K-ras-DCCIK was greater than those of CIK and CTL. CTL induced by K-ras-DCs only inhibited the PANC-1 cells.Conclusions. The k-ras-DC can enhance CIK's proliferation and increase the killing effect on pancreatic cancer cell. The CTLs induced by K-ras-DC can only inhibit PANC-1 cells. In this study, K-ras-DCCIKs also show the specific inhibition to PANC-1 cells, their tumor suppression is almost same with the CTLs, their total tumor inhibitory efficiency is higher than that of the CTLs.
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Meng, Ning, Christophe Glorieux, Yanyu Zhang, Liyun Liang, Peiting Zeng, Wenhua Lu, and Peng Huang. "Oncogenic K-ras Induces Mitochondrial OPA3 Expression to Promote Energy Metabolism in Pancreatic Cancer Cells." Cancers 12, no. 1 (December 25, 2019): 65. http://dx.doi.org/10.3390/cancers12010065.
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K-ras (Kirsten ras GTPase) mutations are oncogenic events frequently observed in many cancer types especially in pancreatic cancer. Although mitochondrial dysfunction has been associated with K-ras mutation, the molecular mechanisms by which K-ras impacts mitochondria and maintains metabolic homeostasis are not fully understood. In this study, we used two K-ras inducible cell systems, human pancreatic epithelial/ K-rasG12D (HPNE/K-rasG12D) and human embryonic kidney cells with tetracycline repressorT-Rex/K-rasG12V, to evaluate the role of oncogenic K-ras in regulating mitochondrial function. Among a panel of genes known to affect mitochondria, only the expression of OPA3 (optic atrophy protein 3) was consistently up-regulated by K-ras activation in both cell lines. Importantly, high expression of OPA3 was also observed in clinical pancreatic cancer tissues. Genetic knockdown of OPA3 caused a significant decrease of energy metabolism, manifested by a suppression of oxygen consumption rate (OCR) and a decrease in cellular ATP content, leading to inhibition of cell proliferation capacity and reduced expression of epithelial–mesenchymal transition (EMT) markers. Our study suggests that OPA3 may promote cellular energy metabolism and its up-regulation in K-ras-driven cancer is likely a mechanism to offset the negative impact of K-ras on mitochondria to maintain energy homeostasis. As such, OPA3 could be a potential target to kill cancer cells with K-ras mutations.
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Ghai, Shruti, Alex Young, and Kuo-Hui Su. "Abstract 3004: Novel effect of Selumetinib-mediated autophagy via HSF1 in K-Ras mutant pancreatic cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3004. http://dx.doi.org/10.1158/1538-7445.am2022-3004.
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Abstract Introduction: K-Ras mutant cancers such as pancreatic cancer are a major cause of cancer-related death and are difficult to treat, with a five-year survival rate of less than 6%. It is reported that oncogenic K-Ras signaling passes through RAF/MEK/ERK pathways. Selumetinib (AZD6244) is a selective MEK inhibitor for K-Ras mutant cancers dependent on mitogen-activated protein kinase (MAPK) signaling pathway and is currently in phase II trials. However, the underlying mechanisms of action are not well known. Autophagy is a self-digest pathway to degrade cellular organelles and macromolecules in maintaining proteome homeostasis, and it is suppressed by the mammalian target of rapamycin complex 1 (mTORC1), a master regulator of translation and autophagy. mTOR activity is known to be activated by AMP-activated protein kinase (AMPK) and negatively regulated by c-Jun N-terminal kinase 1/2 (JNK1/2) MAPK signaling. Autophagy is thought to play protective and suppressive roles in cancer; however, the molecular basis for the relationship between the induction of autophagy and the initiation of pancreatic malignancy is currently unknown. Heat shock factor 1 (HSF1), a key transcription factor involved in proteotoxic stress response via protein-folding. HSF1 plays a pro-oncogenic role in the development of cancer by regulating signaling transduction and translation during tumorigenesis. HSF1 is reportedly hyperactive in pancreatic cancers. AZD6244 reportedly decreases HSF1 phosphorylation at Ser326 and HSF1 expression in melanomas and therefore abates cancer development. However, the detailed mechanism by which HSF1 engages in AZD6244-mediated autophagy in K-Ras mutant human pancreatic cancer is not fully understood. Objectives: This study aims to investigate the role of HSF1 in AZD6244-mediated autophagy in K-Ras mutant human pancreatic cancer. Methods and Results: AZD6244 induces robust autophagy response in human pancreatic cells with hyperactive K-Ras signaling. Simultaneously, AZD6244 reduces HSF1 phosphorylation at Ser326 and HSF1 expression in human pancreatic cancer cells. Intriguingly, genetic deletion of HSF1 induces autophagy under starvation condition. In addition, AZD6244 induces phosphorylation of AMPK Ser172 and JNK1/2 T183/Y185 and decreases mTORC1 activity in human pancreatic cancer cells. Pharmaceutical inhibition of AMPK or genetic deletion of JNK1/2 prevents AZD6244-induced autophagy. Furthermore, HSF1 knockdown induces phosphorylation of Unc-51-like kinase 1(ULK1) Ser555 and decreases ULK Ser757, which is mediated by AMPK and mTOR, respectively. Conclusion: HSF1 plays an integral role in Selumetinib-mediated autophagy through AMPK and/or JNK1/2 signaling in K-Ras mutant human pancreatic cancer cells. Citation Format: Shruti Ghai, Alex Young, Kuo-Hui Su. Novel effect of Selumetinib-mediated autophagy via HSF1 in K-Ras mutant pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3004.
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Carón, Rubén W., Adly Yacoub, Xiaoyu Zhu, Clint Mitchell, Song Iy Han, Takehiko Sasazuki, Senji Shirasawa, Michael P. Hagan, Steven Grant, and Paul Dent. "H-RAS V12–induced radioresistance in HCT116 colon carcinoma cells is heregulin dependent." Molecular Cancer Therapeutics 4, no. 2 (February 1, 2005): 243–55. http://dx.doi.org/10.1158/1535-7163.243.4.2.
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Abstract The abilities of mutated active K-RAS and H-RAS proteins, in an isogenic human carcinoma cell system, to modulate the activity of signaling pathways following exposure to ionizing radiation is unknown. Loss of K-RAS D13 expression in HCT116 colorectal carcinoma cells blunted basal extracellular signal-regulated kinase 1/2 (ERK1/2), AKT, and c-Jun NH2-terminal kinase 1/2 activity. Deletion of the allele to express K-RAS D13 also enhanced expression of ERBB1, ERBB3, and heregulin but nearly abolished radiation-induced activation of all signaling pathways. Expression of H-RAS V12 in HCT116 cells lacking an activated RAS molecule (H-RAS V12 cells) restored basal ERK1/2 and AKT activity to that observed in parental cells but did not restore or alter basal c-jun NH2-terminal kinase 1/2 activity. In parental cells, radiation caused stronger ERK1/2 pathway activation compared with that of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which correlated with constitutive translocation of Raf-1 into the plasma membrane of parental cells. Inhibition of mitogen-activated protein kinase/ERK1/2, but not PI3K, radiosensitized parental cells. In H-RAS V12 cells, radiation caused stronger PI3K/AKT pathway activation compared with that of the ERK1/2 pathway, which correlated with H-RAS V12–dependent translocation of PI3K into the plasma membrane. Inhibition of PI3K, but not mitogen-activated protein kinase/ERK1/2, radiosensitized H-RAS V12 cells. Radiation-induced activation of the PI3K/AKT pathway in H-RAS V12 cells 2 to 24 hours after exposure was dependent on heregulin-stimulated ERBB3 association with membrane-localized PI3K. Neutralization of heregulin function abolished radiation-induced AKT activation and reverted the radiosensitivity of H-RAS V12 cells to those levels found in cells lacking expression of any active RAS protein. These findings show that H-RAS V12 and K-RAS D13 differentially regulate radiation-induced signaling pathway function. In HCT116 cells expressing H-RAS V12, PI3K-dependent radioresistance is mediated by both H-RAS-dependent translocation of PI3K into the plasma membrane and heregulin-induced activation of membrane-localized PI3K via ERBB3.
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Duong, Hong-Quan. "ID:2037 Molecular mechanisms underlying resistance to MEK1/2 inhibitor in BRAF-mutated colorectal cancer." Biomedical Research and Therapy 4, S (September 5, 2017): 68. http://dx.doi.org/10.15419/bmrat.v4is.276.
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Colorectal carcinomas are characterized by multiple genetic alterations, including constitutive Wnt activity and gain-of-function mutations in K-RAS and B-RAF. BRAF encodes a Ser/Thr kinase acting in the Ras/MEK/ERK pathway and the V600E mutation found in 11% of colorectal cancers renders this kinase constitutively active. B-RAF mutated colorectal carcinomas represents a very aggressive entity with a poor prognosis. Understanding the molecular mechanisms activated downstream of mutated B-RAF is urgently needed to design new therapeutic avenues to treat B-ARF mutated colorectal carcinomas and to circumvent resistance to therapies targeting the Ras/Raf/MEK1/ERK1/2 pathway. In a search for candidates that critically contribute to both intrinsic and acquired resistance to MEK1 inhibition in B-RAF mutated colorectal cancer cells, we identified one scaffold protein whose expression is driven by both NF-kB and AP-1 families of transcription factors. This scaffold protein promotes the expression of HER2 and HER3 in colorectal cancer cells subjected to MEK1 or B-RAF inhibition (Selumetinib and Vemurafenib, respectively) and, as such, is critically involved in the intrinsic resistance to these targeted therapies. The same scaffold protein is also strongly induced in B-RAF but not K-RAS mutated colorectal cancer cells showing acquired resistance to MEK1 inhibition. Interfering with the expression of this scaffold protein circumvents both intrinsic and acquired resistance to Selumetinib in B-RAF mutated colorectal cancer cells. Our study defines a new molecular actor critically involved in oncogenic signaling pathways triggered by mutated B-RAF. Our study also defineS new combinatory therapies to better treat B-RAF-mutated colorectal carcinomas.
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Choi, Jung Kyu, Ihn-Sil Kwak, Sae-Bom Yoon, Heeyeong Cho, and Byoung-San Moon. "A Small Molecule Promoting Neural Differentiation Suppresses Cancer Stem Cells in Colorectal Cancer." Biomedicines 10, no. 4 (April 6, 2022): 859. http://dx.doi.org/10.3390/biomedicines10040859.
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Cancer stem cells (CSCs) are a tumor cell subpopulation that drives tumor progression and metastasis, leading to a poor overall survival of patients. In colorectal cancer (CRC), the hyper-activation of Wnt/β-catenin signaling by a mutation of both adenomatous polyposis coli (APC) and K-Ras increases the size of the CSC population. We previously showed that CPD0857 inactivates Wnt/β-catenin signaling by promoting the ubiquitin-dependent proteasomal degradation of β-catenin and Ras proteins, thereby decreasing proliferation and increasing the apoptosis of CRC lines. CPD0857 also decreased the growth and invasiveness of CRC cells harboring mutant K-Ras resistant to EGFR mAb therapy. Here, we show that CPD0857 treatment decreases proliferation and increases the neuronal differentiation of neural progenitor cells (NPCs). CDP0857 effectively reduced the expression of CSC markers and suppressed self-renewal capacity. CPD0857 treatment also inhibited the proliferation and expression of CSC markers in D-K-Ras MT cells carrying K-Ras, APC and PI3K mutations, indicating the inhibition of PI3K/AKT signaling. Moreover, CPD0857-treated xenograft mice showed a regression of tumor growth and decreased numbers of CSCs in tumors. We conclude that CPD0857 could serve as the basis of a drug development strategy targeting CSCs activated through Wnt/β-catenin-Ras MAPK-PI3K/AKT signaling in CRCs.
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Magudia, Kirti, Aurelia Lahoz, and Alan Hall. "K-Ras and B-Raf oncogenes inhibit colon epithelial polarity establishment through up-regulation of c-myc." Journal of Cell Biology 198, no. 2 (July 23, 2012): 185–94. http://dx.doi.org/10.1083/jcb.201202108.
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KRAS, BRAF, and PI3KCA are the most frequently mutated oncogenes in human colon cancer. To explore their effects on morphogenesis, we used the colon cancer–derived cell line Caco-2. When seeded in extracellular matrix, individual cells proliferate and generate hollow, polarized cysts. The expression of oncogenic phosphatidylinositol 3-kinase (PI3KCA H1047R) in Caco-2 has no effect, but K-Ras V12 or B-Raf V600E disrupts polarity and tight junctions and promotes hyperproliferation, resulting in large, filled structures. Inhibition of mitogen-activated protein/extracellular signal–regulated kinase (ERK) kinase blocks the disruption of morphology, as well as the increased levels of c-myc protein induced by K-Ras V12 and B-Raf V600E. Apical polarity is already established after the first cell division (two-cell stage) in Caco-2 three-dimensional cultures. This is disrupted by expression of K-Ras V12 or B-Raf V600E but can be rescued by ribonucleic acid interference–mediated depletion of c-myc. We conclude that ERK-mediated up-regulation of c-myc by K-Ras or B-Raf oncogenes disrupts the establishment of apical/basolateral polarity in colon epithelial cells independently of its effect on proliferation.
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Sprenger, Thilo, Jochen Gaedcke, Lena-Christin Conradi, Peter Jo, Klaus Jung, Tim Beissbarth, Kia Homayounfar, B. Michael Ghadimi, and Torsten Liersch. "Association of CD133 expression levels with the k-ras mutation status in rectal cancers before and after preoperative radiochemotherapy." Journal of Clinical Oncology 31, no. 4_suppl (February 1, 2013): 400. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.400.
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400 Background: The role of the potential stem cell marker CD133 as a predictive or prognostic marker in multimodal rectal cancer treatment is currently under debate. While CD133 has been identified as a prognostic marker in rectal cancers after preoperative radiochemotherapy (RCT) it was recently characterized as a very unspecific feature for colorectal cancer stem cells. We therefore analyzed the association between CD133 expression and mutations in the proto-oncogenes K-Ras and PI3K in rectal cancer patients receiving neoadjuvant RCT. Methods: CD133 expression was evaluated immunhistochemically in pre-treatment biopsies and surgical specimens of 128 patients with locally advanced rectal cancers (cUICC II/III) treated with preoperative RCT within the phase-III German Rectal Cancer Trials. K-Ras mutations were analyzed by sequencing of exons 1, 2, and 3. PI3K mutations were detected by sequencing the p110α subunit (PIK3CA) and correlated with histopathologic parameters, tumor regression and survival. Results: CD133 expression was significantly associated with mutations in the K-Ras gene in both pre-treatment biopsies and post-treatment tumor specimens in uni- and multivariate analyses. However, no significant correlation was observed between CD133 and PI3K mutations. Post-treatment CD133 levels were correlated with neoadjuvant RCT (50.4 Gy/5-FU vs. 50.4 Gy/5-FU+Ox) and tumor regression grading. Anyway, there was no significant association between pre- and post-treatment CD133 expression and disease-free survival. Conclusions: CD133 expression levels are strongly associated with mutations in the K-Ras proto-oncogene in rectal cancers before and after preoperative RCT. Our results strengthen the hypothesis that CD133 is not a specific marker for colorectal stem cells but might be integrated in proliferation pathways like the ras-raf axis.
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Clark, Jennifer, Jessica Freeman, and Howard Donninger. "Loss of RASSF2 Enhances Tumorigencity of Lung Cancer Cells and Confers Resistance to Chemotherapy." Molecular Biology International 2012 (May 24, 2012): 1–8. http://dx.doi.org/10.1155/2012/705948.
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RASSF2 is a novel pro-apoptotic effector of K-Ras that is frequently inactivated in a variety of primary tumors by promoter methylation. Inactivation of RASSF2 enhances K-Ras-mediated transformation and overexpression of RASSF2 suppresses tumor cell growth. In this study, we confirm that RASSF2 and K-Ras form an endogenous complex, validating that RASSF2 is a bona fide K-Ras effector. We adopted an RNAi approach to determine the effects of inactivation of RASSF2 on the transformed phenotype of lung cancer cells containing an oncogenic K-Ras. Loss of RASSF2 expression resulted in a more aggressive phenotype that was characterized by enhanced cell proliferation and invasion, decreased cell adhesion, the ability to grow in an anchorage-independent manner and cell morphological changes. This enhanced transformed phenotype of the cells correlated with increased levels of activated AKT, indicating that RASSF2 can modulate Ras signaling pathways. Loss of RASSF2 expression also confers resistance to taxol and cisplatin, two frontline therapeutics for the treatment of lung cancer. Thus we have shown that inactivation of RASSF2, a process that occurs frequently in primary tumors, enhances the transforming potential of activated K-Ras and our data suggests that RASSF2 may be a novel candidate for epigenetic-based therapy in lung cancer.
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van Houdt, Winan J., Menno T. de Bruijn, Benjamin L. Emmink, Danielle Raats, Frederik J. H. Hoogwater, Inne H. M. Borel Rinkes, and Onno Kranenburg. "Oncogenic K-Ras Activates p38 to Maintain Colorectal Cancer Cell Proliferation during MEK Inhibition." Analytical Cellular Pathology 32, no. 4 (January 1, 2010): 245–57. http://dx.doi.org/10.1155/2010/120143.
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Background: Colon carcinomas frequently contain activating mutations in the K-ras proto-oncogene. K-ras itself is a poor drug target and drug development efforts have mostly focused on components of the classical Ras-activated MEK/ERK pathway. Here we have studied whether endogenous oncogenic K-ras affects the dependency of colorectal tumor cells on MEK/ERK signaling.Methods: K-ras mutant colorectal tumor cell lines C26, HCT116 and L169 were used. K-ras or components of the MEK/ERK and p38 pathway were suppressed by RNA interference (RNAi). MEK was inhibited by U0126. p38 was inhibited by SB203850.Results: MEK inhibition, or suppression of MEK1/2 or ERK1/2 by RNA interference, reduced the proliferation rate of all colorectal cancer cell lines. However, cell proliferation returned to normal after two weeks of chronic inhibition, despite the continued suppression of MEK or ERK. In contrast, K-ras-suppressed tumor cells entered an irreversible senescent-like state following ERK pathway inhibition. MEK inhibition or ERK1/2 suppression caused activation of p38α in a K-ras-dependent manner. Inhibition or suppression of p38α prevented the recovery of K-ras mutant tumor cells during prolonged MEK inhibition.Conclusions: Oncogenic K-ras activates p38α to maintain cell proliferation during MEK inhibition. MEK-targeting therapeutics can create an acquired tumor cell dependency on p38α.
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Padavano, Julianna, Rebecca S. Henkhaus, Hwudaurw Chen, Bethany A. Skovan, Haiyan Cui, and Natalia A. Ignatenko. "Mutant K-RAS Promotes Invasion and Metastasis in Pancreatic Cancer through GTPase Signaling Pathways." Cancer Growth and Metastasis 8s1 (January 2015): CGM.S29407. http://dx.doi.org/10.4137/cgm.s29407.
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Pancreatic ductal adenocarcinoma is one of the most aggressive malignancies, characterized by the local invasion into surrounding tissues and early metastasis to distant organs. Oncogenic mutations of the K-RAS gene occur in more than 90% of human pancreatic cancers. The goal of this study was to investigate the functional significance and downstream effectors of mutant K-RAS oncogene in the pancreatic cancer invasion and metastasis. We applied the homologous recombination technique to stably disrupt K-RAS oncogene in the human pancreatic cell line MiaPaCa-2, which carries the mutant K-RASG12C oncogene in both alleles. Using in vitro assays, we found that clones with disrupted mutant K-RAS gene exhibited low RAS activity, reduced growth rates, increased sensitivity to the apoptosis inducing agents, and suppressed motility and invasiveness. In vivo assays showed that clones with decreased RAS activity had reduced tumor formation ability in mouse xenograft model and increased survival rates in the mouse orthotopic pancreatic cancer model. We further examined molecular pathways downstream of mutant K-RAS and identified RhoA GTP activating protein 5, caveolin-1, and RAS-like small GTPase A (RalA) as key effector molecules, which control mutant K-RAS-dependent migration and invasion in MiaPaCa-2 cells. Our study provides rational for targeting RhoA and RalA GTPase signaling pathways for inhibition of pancreatic cancer metastasis.
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Poorebrahim, Mansour, Mohammad Foad Abazari, Leila Moradi, Behzad Shahbazi, Reza Mahmoudi, Hourieh Kalhor, Hassan Askari, and Ladan Teimoori-Toolabi. "Multi-targeting of K-Ras domains and mutations by peptide and small molecule inhibitors." PLOS Computational Biology 18, no. 4 (April 26, 2022): e1009962. http://dx.doi.org/10.1371/journal.pcbi.1009962.
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K-Ras activating mutations are significantly associated with tumor progression and aggressive metastatic behavior in various human cancers including pancreatic cancer. So far, despite a large number of concerted efforts, targeting of mutant-type K-Ras has not been successful. In this regard, we aimed to target this oncogene by a combinational approach consisting of small peptide and small molecule inhibitors. Based on a comprehensive analysis of structural and physicochemical properties of predominantly K-Ras mutants, an anti-cancer peptide library and a small molecule library were screened to simultaneously target oncogenic mutations and functional domains of mutant-type K-Ras located in the P-loop, switch I, and switch II regions. The selected peptide and small molecule showed notable binding affinities to their corresponding binding sites, and hindered the growth of tumor cells carrying K-RasG12D and K-RasG12C mutations. Of note, the expression of K-Ras downstream genes (i.e., CTNNB1, CCND1) was diminished in the treated Kras-positive cells. In conclusion, our combinational platform signifies a new potential for blockade of oncogenic K-Ras and thereby prevention of tumor progression and metastasis. However, further validations are still required regarding the in vitro and in vivo efficacy and safety of this approach.
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Poorebrahim, Mansour, Mohammad Foad Abazari, Leila Moradi, Behzad Shahbazi, Reza Mahmoudi, Hourieh Kalhor, Hassan Askari, and Ladan Teimoori-Toolabi. "Multi-targeting of K-Ras domains and mutations by peptide and small molecule inhibitors." PLOS Computational Biology 18, no. 4 (April 26, 2022): e1009962. http://dx.doi.org/10.1371/journal.pcbi.1009962.
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K-Ras activating mutations are significantly associated with tumor progression and aggressive metastatic behavior in various human cancers including pancreatic cancer. So far, despite a large number of concerted efforts, targeting of mutant-type K-Ras has not been successful. In this regard, we aimed to target this oncogene by a combinational approach consisting of small peptide and small molecule inhibitors. Based on a comprehensive analysis of structural and physicochemical properties of predominantly K-Ras mutants, an anti-cancer peptide library and a small molecule library were screened to simultaneously target oncogenic mutations and functional domains of mutant-type K-Ras located in the P-loop, switch I, and switch II regions. The selected peptide and small molecule showed notable binding affinities to their corresponding binding sites, and hindered the growth of tumor cells carrying K-RasG12D and K-RasG12C mutations. Of note, the expression of K-Ras downstream genes (i.e., CTNNB1, CCND1) was diminished in the treated Kras-positive cells. In conclusion, our combinational platform signifies a new potential for blockade of oncogenic K-Ras and thereby prevention of tumor progression and metastasis. However, further validations are still required regarding the in vitro and in vivo efficacy and safety of this approach.
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Nkembo, Augustine T., Felix Amissah, Elizabeth Ntantie, Rosemary A. Poku, Olufisayo O. Salako, Offiong Francis Ikpatt, and Nazarius S. Lamango. "Polyisoprenylated Cysteinyl Amide Inhibitors Deplete K-Ras and Induce Caspase-dependent Apoptosis in Lung Cancer Cells." Current Cancer Drug Targets 19, no. 10 (December 23, 2019): 838–51. http://dx.doi.org/10.2174/1568009619666190325144636.
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Background: Non-small cell lung cancers (NSCLC) harboring mutation-induced dysregulation of Ras signaling present some of the most difficult-to-manage cases, since directly targeting the constitutively active mutant Ras proteins has not resulted in clinically useful drugs. Therefore, modulating Ras activity for targeted treatment of cancer remains an urgent healthcare need. Objective: In the current study, we investigated a novel class of compounds, the polyisoprenylated cysteinyl amide inhibitors (PCAIs), for their anticancer molecular mechanisms using the NSCLC cell panel with K-Ras and/or other mutant genes. Methods: The effect of the PCAIs on intracellular K-Ras levels, cell viability, apoptosis, spheroid and colony formation were determined. Results: Treatment of the lung cancer cells with the PCAIs, NSL-RD-035, NSL-BA-036, NSL-BA- 040 and NSL-BA-055 resulted in concentration-dependent cell death in both K-Ras mutant (A549, NCI-H460, and NCI-H1573), N-Ras mutant (NCI-H1299) and other (NCI-H661, NCI-H1975, NCIH1563) NSCLC cells. The PCAIs at 1.0 -10 μM induced the degeneration of 3D spheroid cultures, inhibited clonogenic cell growth and induced marked apoptosis via the extrinsic pathway. The most potent of the PCAIs, NSL-BA-055, at 5 μM induced a seven-fold increase in the activity of caspase- 3/7 and a 75% selective depletion of K-Ras protein levels relative to GAPDH in A549 cells that correlated with PCAIs-induced apoptosis. NSL-BA-040 and NSL-BA-055 also induced the phosphorylation of MAP kinase (ERK 1/2). Conclusion: Taken together, PCAIs may be potentially useful as targeted therapies that suppress NSCLC progression through disruption of Ras-mediated growth signaling.
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Dvory-Sobol, H., T. Kunik, D. Kazanov, M. Rozenblat, E. Cohen Noyman, E. Liberman, and N. Arber. "Selective targeting of K-ras mutated colon cancer cells." Gastroenterology 124, no. 4 (April 2003): A363—A364. http://dx.doi.org/10.1016/s0016-5085(03)81838-3.
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Zhang, Mingquan, Rong Xiang, Christophe Glorieux, and Peng Huang. "PLA2G2A Phospholipase Promotes Fatty Acid Synthesis and Energy Metabolism in Pancreatic Cancer Cells with K-ras Mutation." International Journal of Molecular Sciences 23, no. 19 (October 3, 2022): 11721. http://dx.doi.org/10.3390/ijms231911721.
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Oncogenic K-ras is often activated in pancreatic ductal adenocarcinoma (PDAC) due to frequent mutation (>90%), which drives multiple cellular processes, including alterations in lipid metabolism associated with a malignant phenotype. However, the role and mechanism of the altered lipid metabolism in K-ras-driven cancer remains poorly understood. In this study, using human pancreatic epithelial cells harboring inducible K-rasG12D (HPNE/K-rasG12D) and pancreatic cancer cell lines, we found that the expression of phospholipase A2 group IIA (PLA2G2A) was upregulated by oncogenic K-ras. The elevated expression of PLA2G2A was also observed in pancreatic cancer tissues and was correlated with poor survival of PDAC patients. Abrogation of PLA2G2A by siRNA or by pharmacological inhibition using tanshinone I significantly increased lipid peroxidation, reduced fatty acid synthase (FASN) expression, and impaired mitochondrial function manifested by a decrease in mitochondrial transmembrane potential and a reduction in ATP production, leading to the inhibition of cancer cell proliferation. Our study suggests that high expression of PLA2G2A induced by oncogenic K-ras promotes cancer cell survival, likely by reducing lipid peroxidation through its ability to facilitate the removal of polyunsaturated fatty acids from lipid membranes by enhancing the de novo fatty acid synthesis and energy metabolism to support cancer cell proliferation. As such, PLA2G2A might function as a downstream mediator of K-ras and could be a potential therapeutic target.
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Nastasă, Cristina, Radu Tamaian, Ovidiu Oniga, and Brîndușa Tiperciuc. "5-Arylidene(chromenyl-methylene)-thiazolidinediones: Potential New Agents against Mutant Oncoproteins K-Ras, N-Ras and B-Raf in Colorectal Cancer and Melanoma." Medicina 55, no. 4 (March 31, 2019): 85. http://dx.doi.org/10.3390/medicina55040085.
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Background and objectives: Cancer represents the miscommunication between and within the body cells. The mutations of the oncogenes encoding the MAPK pathways play an important role in the development of tumoral diseases. The mutations of KRAS and BRAF oncogenes are involved in colorectal cancer and melanoma, while the NRAS mutations are associated with melanoma. Thiazolidine-2,4-dione is a versatile scaffold in medicinal chemistry and a useful tool in the development of new antitumoral compounds. The aim of our study was to predict the pharmacokinetic/pharmacodynamic properties, the drug-likeness and lead-likeness of two series of synthetic 5-arylidene(chromenyl-methylene)-thiazolidinediones, the molecular docking on the oncoproteins K-Ras, N-Ras and B-Raf, and to investigate the cytotoxicity of the compounds, in order to select the best structural profile for potential anticancer agents. Materials and Methods: In our paper we studied the cytotoxicity of two series of thiazolidine-2,4-dione derivatives, their ADME-Tox properties and the molecular docking on a mutant protein of K-Ras, two isoforms of N-Ras and an isoform of B-Raf with 16 mutations. Results: The heterocyclic compounds strongly interact with K-Ras and N-Ras right after their posttranslational processing and/or compete with GDP for the nucleotide-binding site of the two GTPases. They are less active against the GDP-bound states of the two targets. All derivatives have a similar binding pattern in the active site of B-Raf. Conclusions: The data obtained encourage the further investigation of the 5-arylidene(chromenyl-methylene)-thiazolidinediones as potential new agents against the oncoproteins K-Ras, N-Ras and B-Raf.
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Wang, Yongsheng, Yu Ma, Dan Li, and Fuchun Guo. "Effect of metformin on the effects of TKI on human lung carcinoma cells harboring KRAS or EGFR-T790M mutation." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e18051-e18051. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e18051.
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e18051 Background: K-ras and egfr-T790M mutation show primary and acquired resistance to EGFR-TKI in non-small cell lung cancer, respectively. The antidiabetic drug metformin has been associated with a decreased incidence and a better prognosis of lung cancer. The affects of metformin on the EGFR-TKI resistance in non-small cell lung cancer remain unknown. Methods: The effects of metformin on EGFR-TKI were investigated in k-ras mutant A549 cells, and egfr-T790M mutant H1975 cells both in virto and in vivo. The proliferation and apoptosis were tested. The underlying mechanisms were also analyzed. Results: Our data showed metformin significantly enhanced the inhibition activity of gefitinib both in A549 and H1975 cells in vitro. At the molecular level, metformin inhibited multiple signaling including LKB1-AMPK-S6K, PI3K-AKT and Raf-MEK-MAPK in a dose-dependent manner. Furthermore, the increased tumor inhibitions were observed in nude mice models of A549 (P<0.05)and H1975 (P<0.01). Conclusions: Metformin can increase the effects of EGFR-TKI in lung adenocarcinoma harboring K-ras and egfr-T790M mutation. Our study may provide a new strategy to overcome the EGFR-TKI resistance in NSCLC.
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Carón, Rubén W., Adly Yacoub, Min Li, Xiaoyu Zhu, Clint Mitchell, Young Hong, William Hawkins, et al. "Activated forms of H-RAS and K-RAS differentially regulate membrane association of PI3K, PDK-1, and AKT and the effect of therapeutic kinase inhibitors on cell survival." Molecular Cancer Therapeutics 4, no. 2 (February 1, 2005): 257–70. http://dx.doi.org/10.1158/1535-7163.257.4.2.
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Abstract The abilities of mutated active RAS proteins to modulate cell survival following exposure to ionizing radiation and small molecule kinase inhibitors were examined. Homologous recombination in HCT116 cells to delete the single allele of K-RAS D13 resulted in a cell line that exhibited an ∼75% reduction in basal extracellular signal-regulated kinase 1/2, AKT, and c-jun-NH2-kinase 1/2 activity. Transfection of cells lacking K-RAS D13 with H-RAS V12 restored extracellular signal-regulated kinase 1/2 and AKT activity to basal levels but did not restore c-jun-NH2-kinase 1/2 phosphorylation. In cells expressing H-RAS V12, radiation caused prolonged intense activation of AKT. Inhibition of H-RAS V12 function, blockade of phosphatidylinositol 3-kinase (PI3K) function using small interfering RNA/small-molecule inhibitors, or expression of dominant-negative AKT abolished radiation-induced AKT activation, and radiosensitized these cells. Inhibition of PI3K function did not significantly radiosensitize parental HCT116 cells. Inhibitors of the AKT PH domain including perifosine, SH-(5, 23-25) and ml-(14-16) reduced the plating efficiency of H-RAS V12 cells in a dose-dependent fashion. Inhibition of AKT function using perifosine enhanced radiosensitivity in H-RAS V12 cells, whereas the SH and ml series of AKT PH domain inhibitors failed to promote radiation toxicity. In HCT116 H-RAS V12 cells, PI3K, PDK-1, and AKT were membrane associated, whereas in parental cells expressing K-RAS D13, only PDK-1 was membrane bound. In H-RAS V12 cells, membrane associated PDK-1 was phosphorylated at Y373/376, which was abolished by the Src family kinase inhibitor PP2. Inhibition of PDK-1 function using the PH domain inhibitor OSU-03012 or using PP2 reduced the plating efficiency of H-RAS V12 cells and profoundly increased radiosensitivity. OSU-03012 and PP2 did not radiosensitize and had modest inhibitory effects on plating efficiency in parental cells. A small interfering RNA generated against PDK1 also radiosensitized HCT116 cells expressing H-RAS V12. Collectively, our data argue that molecular inhibition of AKT and PDK-1 signaling enhances the radiosensitivity of HCT116 cells expressing H-RAS V12 but not K-RAS D13. Small-molecule inhibitory agents that blocked stimulated and/or basal PDK-1 and AKT function profoundly reduced HCT116 cell survival but had variable effects at enhancing tumor cell radiosensitivity.
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Cho, Kwang-jin, Darren E. Casteel, Priyanka Prakash, Lingxiao Tan, Dharini van der Hoeven, Angela A. Salim, Choel Kim, et al. "AMPK and Endothelial Nitric Oxide Synthase Signaling Regulates K-Ras Plasma Membrane Interactions via Cyclic GMP-Dependent Protein Kinase 2." Molecular and Cellular Biology 36, no. 24 (October 3, 2016): 3086–99. http://dx.doi.org/10.1128/mcb.00365-16.
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K-Ras must localize to the plasma membrane and be arrayed in nanoclusters for biological activity. We show here that K-Ras is a substrate for cyclic GMP-dependent protein kinases (PKGs). In intact cells, activated PKG2 selectively colocalizes with K-Ras on the plasma membrane and phosphorylates K-Ras at Ser181 in the C-terminal polybasic domain. K-Ras phosphorylation by PKG2 is triggered by activation of AMP-activated protein kinase (AMPK) and requires endothelial nitric oxide synthase and soluble guanylyl cyclase. Phosphorylated K-Ras reorganizes into distinct nanoclusters that retune the signal output. Phosphorylation acutely enhances K-Ras plasma membrane affinity, but phosphorylated K-Ras is progressively lost from the plasma membrane via endocytic recycling. Concordantly, chronic pharmacological activation of AMPK → PKG2 signaling with mitochondrial inhibitors, nitric oxide, or sildenafil inhibits proliferation of K-Ras-positive non-small cell lung cancer cells. The study shows that K-Ras is a target of a metabolic stress-signaling pathway that can be leveraged to inhibit oncogenic K-Ras function.
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Fleming, Jason B., Guo-Liang Shen, Shane E. Holloway, Mishel Davis, and Rolf A. Brekken. "Molecular Consequences of Silencing Mutant K-ras in Pancreatic Cancer Cells: Justification for K-ras–Directed Therapy." Molecular Cancer Research 3, no. 7 (July 2005): 413–23. http://dx.doi.org/10.1158/1541-7786.mcr-04-0206.
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Esteller, M., S. González, R. A. Risques, E. Marcuello, R. Mangues, J. R. Germà, J. G. Herman, G. Capellà, and M. A. Peinado. "K-rasandp16Aberrations Confer Poor Prognosis in Human Colorectal Cancer." Journal of Clinical Oncology 19, no. 2 (January 15, 2001): 299–304. http://dx.doi.org/10.1200/jco.2001.19.2.299.
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PURPOSE: Mutations in the K-ras gene are frequent in human cancer. ras activation in primary cells results in a cellular senescence phenotype that is precluded by inactivation of p16. At the clinical level, this may imply a differential behavior for tumors with alternative or cooperative activation of K-ras function and impairment of p16 pathways.PATIENTS AND METHODS: We have determined the presence of mutations in the K-ras gene and the methylation status of p16 promoter in a series of 119 prospectively collected colorectal carcinomas. p53 mutations and p14 alternative reading frame methylation status were also assessed. Associations with survival were investigated.RESULTS: K-ras mutations were present in 44 (38%) of 115 cases, and p16 methylation was present in 42 (37%) of 113 cases. p53 mutations were detected in 50% (56 of 115) and p14 methylation in 29% (32 of 112) of cases. K-ras and p16 alterations were independent genetic events. Presence of K-ras or p16 genetic alterations (analyzed independently) was associated with shorter survival, although differences were not statistically significant. Cox analysis of the two variables combined showed a diminished survival as the results of an interaction between p16 and K-ras. Alternative alteration of K-ras and p16 genes was an independent prognostic factor in human colorectal cancer in univariate and multivariate analysis. Differences were maintained when cases undergoing radical surgery and without distant metastases were considered.CONCLUSION: These results suggest that the combined K-ras and p16 analyses may be of prognostic use in human colorectal cancer.
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Wahlstrom, Annika M., Briony A. Cutts, Meng Liu, Annika Lindskog, Christin Karlsson, Anna-Karin M. Sjogren, Karin M. E. Andersson, Stephen G. Young, and Martin O. Bergo. "Inactivating Icmt ameliorates K-RAS–induced myeloproliferative disease." Blood 112, no. 4 (August 15, 2008): 1357–65. http://dx.doi.org/10.1182/blood-2007-06-094060.
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Abstract Hyperactive signaling through the RAS proteins is involved in the pathogenesis of many forms of cancer. The RAS proteins and many other intracellular signaling proteins are either farnesylated or geranylgeranylated at a carboxyl-terminal cysteine. That isoprenylcysteine is then carboxyl methylated by isoprenylcysteine carboxyl methyltransferase (ICMT). We previously showed that inactivation of Icmt mislocalizes the RAS proteins away from the plasma membrane and blocks RAS transformation of mouse fibroblasts, suggesting that ICMT could be a therapeutic target. However, nothing is known about the impact of inhibiting ICMT on the development of malignancies in vivo. In the current study, we tested the hypothesis that inactivation of Icmt would inhibit the development or progression of a K-RAS–induced myeloproliferative disease in mice. We found that inactivating Icmt reduced splenomegaly, the number of immature myeloid cells in peripheral blood, and tissue infiltration by myeloid cells. Moreover, in the absence of Icmt, the ability of K-RAS–expressing hematopoietic cells to form colonies in methylcellulose without exogenous growth factors was reduced dramatically. Finally, inactivating Icmt reduced lung tumor development and myeloproliferation phenotypes in a mouse model of K-RAS–induced cancer. We conclude that inactivation of Icmt ameliorates phenotypes of K-RAS–induced malignancies in vivo.
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Meinohl, Christopher, Sarah J. Barnard, Karin Fritz-Wolf, Monika Unger, Andreea Porr, Marisa Heipel, Stefanie Wirth, et al. "Galectin-8 binds to the Farnesylated C-terminus of K-Ras4B and Modifies Ras/ERK Signaling and Migration in Pancreatic and Lung Carcinoma Cells." Cancers 12, no. 1 (December 20, 2019): 30. http://dx.doi.org/10.3390/cancers12010030.
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K-Ras is the most prominent driver of oncogenesis and no effective K-Ras inhibitors have been established despite decades of intensive research. Identifying new K-Ras-binding proteins and their interaction domains offers the opportunity for defining new approaches in tackling oncogenic K-Ras. We have identified Galectin-8 as a novel, direct binding protein for K-Ras4B by mass spectrometry analyses and protein interaction studies. Galectin-8 is a tandem-repeat Galectin and it is widely expressed in lung and pancreatic carcinoma cells. siRNA-mediated depletion of Galectin-8 resulted in increased K-Ras4B content and ERK1/2 activity in lung and pancreatic carcinoma cells. Moreover, cell migration and cell proliferation were inhibited by the depletion of Galectin-8. The K-Ras4B–Galectin-8 interaction is indispensably associated with the farnesylation of K-Ras4B. The lysine-rich polybasic domain (PBD), a region that is unique for K-Ras4B as compared to H- and N-Ras, stabilizes the interaction and accounts for the specificity. Binding assays with the deletion mutants of Galectin-8, comprising either of the two carbohydrate recognition domains (CRD), revealed that K-Ras4B only interacts with the N-CRD, but not with the C-CRD. Structural modeling uncovers a potential binding pocket for the hydrophobic farnesyl chain of K-Ras4B and a cluster of negatively charged amino acids for interaction with the positively charged lysine residues in the N-CRD. Our results demonstrate that Galectin-8 is a new binding partner for K-Ras4B and it interacts via the N-CRD with the farnesylated PBD of K-Ras, thereby modulating the K-Ras effector pathways as well as cell proliferation and migration.
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P. R. "Ras K-oncogen and antigens on ovarian carcinoma cells." Medical Oncology and Tumor Pharmacotherapy 2, no. 2 (June 1985): 117. http://dx.doi.org/10.1007/bf02934860.
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Orlandi, Armando, Mariantonietta Di Salvatore, Michele Basso, Cinzia Bagalà, Antonia Strippoli, Francesca Plastino, Enzo Dadduzio, et al. "ERCC1, KRAS mutation, and oxaliplatin sensitivity in colorectal cancer: Old dogs and new tricks." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 489. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.489.
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489 Background: Oxaliplatin is widely used in metastatic colorectal cancer, but currently there are not valid predictors of response to this drug. In our recent retrospective clinical study we have shown a greater efficacy of Oxaliplatin in patients with metastatic colorectal cancer with mutated (mt) K-RAS. We hypothesized that the mutational status of K-RAS could influence the expression of ERCC1, one of the main mechanisms of Oxaliplatin resistance. Methods: We used four cell lines of colorectal cancer: two K-RAS wild type (wt) (HCT-8 and HT-29) and two K-RAS mt (SW620 and SW480). We evaluated the sensitivity of these cell lines to Oxaliplatin by MTT-test and the ERCC1 levels before and after 24 h exposure to Oxaliplatin by Real-Time PCR. We silenced K-RAS in a K-RAS mt cell line to evaluate the impact on Oxaliplatin sensitivity and ERCC1 levels. We also silenced ERCC1 in order to confirm the importance of this protein as a Oxaliplatin resistance factor. Results: The K-RAS mt cell lines were more sensitive to Oxaliplatin (OR 2.68; IC 95% 1.511-4.757 p<0.001). The basal levels of ERCC1 did not show significant differences between K-RAS mt and wt cell line, however, after 24 h exposure to Oxaliplatin, only the K-RAS wt lines showed the ability to induce ERCC1, with a statistically significant difference (OR 42.9 IC 95% 17.260-106.972 p<0.0005). The silencing of K-RAS in K-RAS mt cell lines demonstrated to reduce sensitivity to Oxaliplatin associated with the acquisition of the ability to induce ERCC1. The silencing of ERCC1 in K-RAS wt cell lines enhance the sensibility to Oxaliplatin. Conclusions: The K-RAS mutated cell lines were more sensitive to Oxaliplatin. This feature seems to be secondary to the inability of these cells to induce ERCC1 after exposure to Oxaliplatin. K-RAS can thus be a predictor of response to Oxaliplatin in colorectal cancer representing a surrogate for ability to induce ERCC1.
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Romano, David, Helene Maccario, Carolanne Doherty, Niall P. Quinn, Walter Kolch, and David Matallanas. "The Differential Effects of Wild-Type and Mutated K-Ras on MST2 Signaling Are Determined by K-Ras Activation Kinetics." Molecular and Cellular Biology 33, no. 9 (March 4, 2013): 1859–68. http://dx.doi.org/10.1128/mcb.01414-12.
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K-Ras is frequently mutated in human cancers. Mutant (mt) K-Ras can stimulate both oncogenic transformation and apoptosis through activation of extracellular signal-regulated kinase (ERK) and AKT pathways and the MST2 pathway, respectively. The biological outcome is determined by the balance and cross talk between these pathways. In colorectal cancer (CRC), a K-Ras mutation is negatively correlated with MST2 expression, as mt K-Ras can induce apoptosis by activating the MST2 pathway. However, wild-type (wt) K-Ras can prevent the activation of the MST2 pathway upon growth factor stimulation and enable transformation by mt K-Ras in CRC cells that express MST2. Here we have investigated the mechanism by which wt and mt K-Ras differentially regulate the MST2 pathway and MST2-dependent apoptosis. The ability of K-Ras to activate MST2 and MST2-dependent apoptosis is determined by the differential activation kinetics of mt K-Ras and wt K-Ras. Chronic activation of K-Ras by mutation or overexpression of Ras exchange factors results in the activation of MST2 and LATS1, increased MST2-LATS1 complex formation, and apoptosis. In contrast, transient K-Ras activation upon epidermal growth factor (EGF) stimulation prevents the formation of the MST2-LATS1 complex in an AKT-dependent manner. Our data suggest that the close relationship between Ras prosurvival and proapoptotic signaling is coordinated via the differential regulation of the MST2-LATS1 interaction by transient and chronic stimuli.
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zhang, Mingquan, and Peng huang. "Abstract 5804: The inhibition of PLA2G2A decreases K-ras-driven pancreatic cancer growth and migration through damaging cell membrane and mitochondria function." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5804. http://dx.doi.org/10.1158/1538-7445.am2022-5804.
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Abstract The activation of oncogenic K-ras by mutations may stimulate multiple cellular processes including lipids modification. However, the mechanisms by which K-ras affects lipid metabolism remain poorly understood. In this study, we found that PLA2G2A, an enzyme that hydrolyzes membrane phospholipids at sn-2 position to release polyunsaturated fatty acids (PUFA), was up-regulated by K-ras activation and its high expression was correlated with poor survival of patients with pancreatic ductal adenocarcinoma (PDAC). Abrogation of PLA2G2A by siRNA silencing or pharmacological inhibition significantly suppressed the proliferation of K-ras-driven cancer cells, as evidenced by inhibition of cell growth and loss of colony formation capacity. Suppression of PLA2G2A could also decrease K-ras-driven PDAC cell migration. Mechanistic study showed that PLA2G2A inhibition rendered cells vulnerability to lipid peroxidation, likely due to accumulation of excessive PUFA in the membranes. Such alterations resulted in membrane damage and mitochondrial dysfunction with elevated ROS, leading to a reduction in energy production and a decrease in acetyl-CoA, which further compromised de novo lipid biosynthesis. Our study suggests that PLA2G2A-mediated cell membrane remodeling plays an important role in cell survival and proliferation in during K-ras-driven cancer, and that PLA2G2 could be a potential therapeutic target for pancreatic cancer treatment. Citation Format: Mingquan zhang, Peng huang. The inhibition of PLA2G2A decreases K-ras-driven pancreatic cancer growth and migration through damaging cell membrane and mitochondria function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5804.
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Yuen, Hiu-Fung, Olga Abramczyk, Grant Montgomery, Ka-Kui Chan, Yu-Han Huang, Takehiko Sasazuki, Senji Shirasawa, et al. "Impact of oncogenic driver mutations on feedback between the PI3K and MEK pathways in cancer cells." Bioscience Reports 32, no. 4 (July 4, 2012): 413–22. http://dx.doi.org/10.1042/bsr20120050.
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Inhibition of the PI3K (phosphoinositide 3-kinase)/Akt/mTORC1 (mammalian target of rapamycin complex 1) and Ras/MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase]/ERK pathways for cancer therapy has been pursued for over a decade with limited success. Emerging data have indicated that only discrete subsets of cancer patients have favourable responses to these inhibitors. This is due to genetic mutations that confer drug insensitivity and compensatory mechanisms. Therefore understanding of the feedback mechanisms that occur with respect to specific genetic mutations may aid identification of novel biomarkers that predict patient response. In the present paper, we show that feedback between the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways is cell-line-specific and highly dependent on the activating mutation of K-Ras or overexpression c-Met. We found that cell lines exhibited differential signalling and apoptotic responses to PD184352, a specific MEK inhibitor, and PI103, a second-generation class I PI3K inhibitor. We reveal that feedback from the PI3K/Akt/mTORC1 to the Ras/MEK/ERK pathway is present in cancer cells harbouring either K-Ras activating mutations or amplification of c-Met but not the wild-type counterparts. Moreover, we demonstrate that inhibition of protein phosphatase activity by OA (okadaic acid) restored PI103-mediated feedback in wild-type cells. Together, our results demonstrate a novel mechanism for feedback between the PI3K/Akt/mTORC1 and the Ras/MEK/ERK pathways that only occurs in K-Ras mutant and c-Met amplified cells but not the isogenic wild-type cells through a mechanism that may involve inhibition of a specific endogenous phosphatase(s) activity. We conclude that monitoring K-Ras and c-Met status are important biomarkers for determining the efficacy of PI103 and other PI3K/Akt inhibitors in cancer therapy.
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Siddiqui, Farid Ahmad, Hanna Parkkola, Vladimir Vukic, Christina Oetken-Lindholm, Alok Jaiswal, Alexandros Kiriazis, Karolina Pavic, Tero Aittokallio, Tiina A. Salminen, and Daniel Abankwa. "Novel Small Molecule Hsp90/Cdc37 Interface Inhibitors Indirectly Target K-Ras-Signaling." Cancers 13, no. 4 (February 23, 2021): 927. http://dx.doi.org/10.3390/cancers13040927.
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The ATP-competitive inhibitors of Hsp90 have been tested predominantly in kinase addicted cancers; however, they have had limited success. A mechanistic connection between Hsp90 and oncogenic K-Ras is not known. Here, we show that K-Ras selectivity is enabled by the loss of the K-Ras membrane nanocluster modulator galectin-3 downstream of the Hsp90 client HIF-1α. This mechanism suggests a higher drug sensitivity in the context of KRAS mutant, HIF-1α-high and/or Gal3-high cancer cells, such as those found, in particular, in pancreatic adenocarcinoma. The low toxicity of conglobatin further indicates a beneficial on-target toxicity profile for Hsp90/Cdc37 interface inhibitors. We therefore computationally screened >7 M compounds, and identified four novel small molecules with activities of 4 μM–44 μM in vitro. All of the compounds were K-Ras selective, and potently decreased the Hsp90 client protein levels without inducing the heat shock response. Moreover, they all inhibited the 2D proliferation of breast, pancreatic, and lung cancer cell lines. The most active compounds from each scaffold, furthermore, significantly blocked 3D spheroids and the growth of K-Ras-dependent microtumors. We foresee new opportunities for improved Hsp90/Cdc37 interface inhibitors in cancer and other aging-associated diseases.
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Chiaradonna, F., C. Magnani, E. Sacco, R. Manzoni, L. Alberghina, and M. Vanoni. "Acquired glucose sensitivity of k-ras transformed fibroblasts." Biochemical Society Transactions 33, no. 1 (February 1, 2005): 297–99. http://dx.doi.org/10.1042/bst0330297.
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Mutational activation of the ras gene is critical for the onset of different malignant phenotypes. We constructed a dominant negative mutant (GEF-DN) of a Ras activator protein (guanine nucleotide-exchange factor) that upon over-expression in k-ras transformed NIH 3T3 fibroblasts strongly reduces intracellular Ras•GTP, reverting these cells to wild-type phenotype for morphology, anchorage-independent growth and reduction of tumour formation in nude mice. Here we review evidence showing that the enhanced proliferation potential of NIH-ras cells requires high initial glucose concentration in the medium and sustained Ras pathway activation. The exquisite sensitivity of NIH-ras fibroblasts to a shortage in nutrient and energy supply highlights an acquired fragility of cancer cells that may be exploited for therapeutic purposes.
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Subbarayan, Karthikeyan, Sandra Leisz, Chiara Massa, Sravankumar Balina, Anja Müller, Claudia Wickenhauser, and Barbara Seliger. "828 Improved growth properties and immune surveillance in K-RAS G12V-transformed cells through overexpression of biglycan." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A879. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0828.
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BackgroundThe extracellular matrix protein biglycan (BGN) plays an essential role in matrix assembly, cellular migration, adhesion, proliferation and apoptosis. Recently, BGN expression has been shown to be impaired upon HER-2/neu overexpression, which was associated with an up-regulation of MHC class I surface expression. However, there exists no information about the link between K-RAS-mediated immune escape and BGN expression.MethodsIn vitro models of human K-RAS G12V transformed mouse fibroblasts and two human colorectal carcinoma (CRC) cell lines carrying a K-RAS G12V mutation (RKO and SW480) were used for the analysis of BGN expression by qPCR and Western blot. At the same time, the major histocompatibility complex (MHC) class I surface expression, as well as CD4+ and CD8+ cells, were determined by flow cytometry. The different K-RAS G12V cells and respective controls were stably transfected with BGN. Growth properties were analyzed by proliferation, migration and invasion assays. Luciferase reporter assays were used to determine the transcriptional regulation of MHC class I APM components. Tumorgenicity of BGN transfectants in comparison to control cells was evaluated by injection of respective transfectants s.c. into mice and tumor growth was monitored over time.ResultsBoth murine and human K-RAS G12V cells express low levels of BGN compared to control cells. Overexpression of BGN caused an inhibition of cell proliferation, a diminished anchorage-independent growth and a reduced migration rate. The altered in vitro growth properties of BGNhigh K-RAS G12V+ correlated with a delayed tumor growth and a reduced frequency of tumor formation in vivo. Restoration of BGN expression increased the expression of decorin as well as enhanced MHC class I expression in K-RAS G12V-transformed cells. This is due to a BGN-induced transcriptional upregulation of major components of the MHC class I antigen processing machinery (APM), such as the transporter associated with antigen processing TAP1, TAP2 and LMP2, in BGN transfectants of K-RAS G12V+ cells. The results were further supported by the fact that mice bearing tumors induced by BGNhigh K-RAS G12V+ cells showed a reduced MHC class I expression, which was associated with an enhanced frequency of CD8+ and CD4+ cells in the peripheral blood.ConclusionsOur data provide evidence that (i) proteoglycan signatures are modulated by K-RAS G12V transformation, (ii) loss of proteoglycan expression is directly or indirectly involved in immune escape of K-RAS G12V overexpressing tumor cells and (iii) BGN overexpression and enhanced basal decorin expression results in altered growth properties of K-RAS G12V cells. Thus, the reduced migration rate and restoration of MHC class I surface expression by BGN or other proteoglycans are important features for their anti-tumorigenic properties in K-RAS G12-transformed tumor cells including colorectal cancers.AcknowledgementsThe project is supported by Wilhelm-Sander-Stiftung (No: 2019.076.1).ConsentNot applicable
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Vatan, Ozgur, Rahmi Bilaloglu, Berrin Tunca, Gulsah Cecener, Cengiz Gebitekin, Unal Egeli, Tahsin Yakut, and Nur Urer. "Low Frequency of p53AND k-ras Codon 12 Mutations in Non-Small Cell Lung Carcinoma(NSCLC) Tumors and Surgical Margins." Tumori Journal 93, no. 5 (September 2007): 473–77. http://dx.doi.org/10.1177/030089160709300511.
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Aims and Background Lung cancer is one of the most common cancers and has became a predominant cause of cancer-related death throughout the world. The k-ras codon 12 mutation, which is the most common lung cancer mutation, is found in 15 to 30% of all lung cancers. Furthermore, the p53 gene has a very important role in the biological properties of tumor cells, and it is mutated in about 50% of non-small cell lung cancers. Residual tumor cells remain in surgical margins diagnosed as tumor free by histopathological techniques, and they can play a role in forming any local recurrence. Molecular methods may be exploited that are sensitive enough to detect small numbers of tumor cells. Methods In the present study, we examined p53 gene mutations and k-ras codon 12 mutations from the tumor samples and surgical margins of 34 non-small-cell lung cancer patients. P53 gene mutations were analyzed by single strand conformational polymorphism analysis, heterodublex analysis and DNA sequencing. K-ras codon 12 mutations were analyzed by the mutagenic PCR-restricted fragment length polymorphism method. Results A p53 mutation was detected only in primary tumors of 3 out of 34 patients (8.82%). These mutations were clustered in exon 5. Moreover, a k-ras codon 12 mutation was detected in both the primary tumor and the surgical margin tissues of 2 out of 34 patients (5.88%). Conclusions The detected mutation rate was low, in the range given in the literature. We think that different mechanisms related to other genes and individual genetic differences might play a role in cancer formation in our study group. We believe that molecular studies are necessary to identify biomarkers and to determine genetic alterations in histopathologically normal surgical margins.
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Somers, V. A., A. M. Pietersen, P. H. Theunissen, and F. B. Thunnissen. "Detection of K-ras point mutations in sputum from patients with adenocarcinoma of the lung by point-EXACCT." Journal of Clinical Oncology 16, no. 9 (September 1998): 3061–68. http://dx.doi.org/10.1200/jco.1998.16.9.3061.
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PURPOSE Kirsten ras (K-ras) point mutations are found in 30% to 56% of pulmonary adenocarcinomas by means of highly sensitive techniques. Recently, the Point-EXACCT (point mutation detection using exonuclease amplification coupled capture technique) method was described, which detected one cell with a mutation in 15,000 normal cells. The aim of this study was to examine whether K-ras point mutations could be found with this rapid method in the sputum of patients with adenocarcinoma of the lung. PATIENTS AND METHODS DNA from paraffin-embedded adenocarcinoma and corresponding sputum samples were analyzed for mutations of the K-ras gene. Twenty-eight biopsy specimens and 54 sputum samples of 22 patients were used for amplification and K-ras codon 12 point mutation detection. RESULTS In 11 of 22 patients (50%), a mutation in K-ras codon 12 was shown in the tumor sample. In five of 11 patients (45%) with a K-ras mutation in the tumor, the same type of mutation was identified in at least one sputum sample. A mutation could not be detected in any of the sputum samples from patients with a K-ras-negative tumor. Time between K-ras point mutation detection in sputum and clinical diagnosis of lung cancer varied from 1 month to almost 4 years. In two of the five patients with K-ras-positive sputum specimens, malignant cells were found with cytologic examination. CONCLUSION Point-EXACCT is suitable for the detection of K-ras point mutations in sputum samples of patients with adenocarcinoma of the lung. This approach may be an important adjunct to cytology in the early diagnosis of lung cancer.
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Orlandi, Armando, Mariantonietta Di Salvatore, Michele Basso, Cinzia Bagalà, Antonia Strippoli, Francesca Plastino, Enzo Dadduzio, et al. "ERCC1, KRAS mutation, redox status, and oxaliplatin sensitivity in colorectal cancer: “Radical” change in an old model." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e14156-e14156. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e14156.
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e14156 Background: Oxaliplatin (Oxa) is widely used in metastatic colorectal cancer, but currently there are not valid predictors of response to this drug. In our recent retrospective clinical study we have shown a greater efficacy of Oxa in patients with metastatic colorectal cancer with mutated (mt) K-RAS. We hypothesized that the mutational status of K-RAS could influence the expression of ERCC1 and cellular Redox status. Methods: We used four cell lines of colorectal cancer: two K-RAS wild type (wt) (HCT-8, HT-29) and two K-RAS mt (SW620, SW480). We evaluated the sensitivity of these cell lines to Oxa by MTT-test and the ERCC1 levels before and after 24h exposure to Oxa by RT-PCR. We silenced K-RAS in a K-RAS mt cell lines to evaluate the impact on Oxa sensitivity and ERCC1 levels. We also silenced ERCC1 in order to confirm the importance of this protein as a Oxa resistance factor. Cellular oxidative stress was determined by DCFDA. Results: The K-RAS mt cell lines were more sensitive to Oxa (p<0.001). The basal levels of ERCC1 did not show significant differences between K-RAS mt and wt cell line, however, after 24h exposure to Oxa, only the K-RAS wt lines showed the ability to induce ERCC1, with a statistically significant difference (p<0.005). The silencing of K-RAS in K-RAS mt cell lines (SW620s) demonstrated to reduce sensitivity to Oxa associated with the acquisition of the ability to induce ERCC1. The silencing of ERCC1 in K-RAS wt cell lines enhance the sensibility to Oxa. The levels of reactive oxygen species were higher in K-RAS mt cell lines. The Pearson correlation test showed a statistically significant relationship between basal levels of ROS and sensitivity to Oxa ("r" -0,988, p<0.01). The baseline levels of ROS were higher SW620 than the line SW620s. The administration of Oxa in these cell lines resulted in a statistically higher fluorescence index in SW620 versus SW620s (p<0.003). Conclusions: The K-RAS mutated cell lines were more sensitive to Oxa. This feature seems to be secondary to the inability of these cells to induce ERCC1 after exposure to Oxa and to the synergism between K-RAS mutation and Oxa in increasing oxidative stress. K-RAS can thus be a predictor of response to Oxa in colorectal cancer.
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Wu, Han-Tsang, Yi-En Liu, Kai-Wen Hsu, Yu-Fen Wang, Ya-Chi Chan, Yeh Chen, and Dar-Ren Chen. "MLL3 Induced by Luteolin Causes Apoptosis in Tamoxifen-Resistant Breast Cancer Cells through H3K4 Monomethylation and Suppression of the PI3K/AKT/mTOR Pathway." American Journal of Chinese Medicine 48, no. 05 (January 2020): 1221–41. http://dx.doi.org/10.1142/s0192415x20500603.
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Tamoxifen is one of the most common hormone therapy drug for estrogen receptor (ER)-positive breast cancer. Tumor cells with drug resistance often cause recurrence and metastasis in cancer patients. Luteolin is a natural compound found from various types of vegetables and exhibit anticancer activity in different cancers. This study demonstrated that luteolin inhibits the proliferation and induces apoptosis of tamoxifen-resistant ER-positive breast cancer cells. Luteolin also causes cell cycle arrest at the G2/M phase and decreases mitochondrial membrane potential. Besides, luteolin reduces the levels of activated PI3K/AKT/mTOR signaling pathway. The combination treatment of luteolin and PI3K, AKT, or mTOR inhibitors synergistically increases apoptosis in tamoxifen-resistant ER-positive breast cancer cells. Ras gene family (K-Ras, H-Ras, and N-Ras), an activator of PI3K, was transcriptionally repressed by luteolin via induction of tumor suppressor mixed-lineage leukemia 3 (MLL3) expression. MLL3 increases the level of monomethylation of Histone 3 Lysine 4 on the enhancer and promoter region of Ras genes, thus causes repression of Ras expressions. Our finding implies that luteolin was a promising natural agent against tamoxifen resistance of breast cancer.
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Kim, Jung-Sik, Carolyn Lee, Aaron Foxworth, and Todd Waldman. "B-Raf Is Dispensable for K-Ras-Mediated Oncogenesis in Human Cancer Cells 1." Cancer Research 64, no. 6 (March 15, 2004): 1932–37. http://dx.doi.org/10.1158/0008-5472.can-03-3862.
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Manoharan, Ganesh Babu, Sunday Okutachi, and Daniel Abankwa. "Potential of phenothiazines to synergistically block calmodulin and reactivate PP2A in cancer cells." PLOS ONE 17, no. 5 (May 26, 2022): e0268635. http://dx.doi.org/10.1371/journal.pone.0268635.
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Phenothiazines (PTZ) were developed as inhibitors of monoamine neurotransmitter receptors, notably dopamine receptors. Because of this activity they have been used for decades as antipsychotic drugs. In addition, they possess significant anti-cancer properties and several attempts for their repurposing were made. However, their incompletely understood polypharmacology is challenging. Here we examined the potential of the PTZ fluphenazine (Flu) and its mustard derivative (Flu-M) to synergistically act on two cancer associated targets, calmodulin (CaM) and the tumor suppressor protein phosphatase 2A (PP2A). Both proteins are known to modulate the Ras- and MAPK-pathway, cell viability and features of cancer cell stemness. Consistently, we show that the combination of a CaM inhibitor and the PP2A activator DT-061 synergistically inhibited the 3D-spheroid formation of MDA-MB-231 (K-Ras-G13D), NCI-H358 (K-Ras-G12C) and A375 (B-raf-V600E) cancer cells, and increased apoptosis in MDA-MB-231. We reasoned that these activities remain combined in PTZ, which were the starting point for PP2A activator development, while several PTZ are known CaM inhibitors. We show that both Flu and Flu-M retained CaM inhibitory activity in vitro and in cells, with a higher potency of the mustard derivative in cells. In line with the CaM dependence of Ras plasma membrane organization, the mustard derivative potently reduced the functional membrane organization of oncogenic Ras, while DT-061 had a negligible effect. Like DT-061, both PTZ potently decreased c-MYC levels, a hallmark of PP2A activation. Benchmarking against the KRAS-G12C specific inhibitor AMG-510 in MIA PaCa-2 cells revealed a higher potency of Flu-M than combinations of DT-061 and a CaM inhibitor on MAPK-output and a strong effect on cell proliferation. While our study is limited, our results suggest that improved PTZ derivatives that retain both, their CaM inhibitory and PP2A activating properties, but have lost their neurological side-effects, may be interesting to pursue further as anti-cancer agents.
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Wiechmann, Svenja, Pierre Maisonneuve, Britta M. Grebbin, Meike Hoffmeister, Manuel Kaulich, Hans Clevers, Krishnaraj Rajalingam, et al. "Conformation-specific inhibitors of activated Ras GTPases reveal limited Ras dependency of patient-derived cancer organoids." Journal of Biological Chemistry 295, no. 14 (February 20, 2020): 4526–40. http://dx.doi.org/10.1074/jbc.ra119.011025.
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The small GTPases H, K, and NRAS are molecular switches indispensable for proper regulation of cellular proliferation and growth. Several mutations in the genes encoding members of this protein family are associated with cancer and result in aberrant activation of signaling processes caused by a deregulated recruitment of downstream effector proteins. In this study, we engineered variants of the Ras-binding domain (RBD) of the C-Raf proto-oncogene, Ser/Thr kinase (CRAF). These variants bound with high affinity with the effector-binding site of Ras in an active conformation. Structural characterization disclosed how the newly identified RBD mutations cooperate and thereby enhance affinity with the effector-binding site in Ras compared with WT RBD. The engineered RBD variants closely mimicked the interaction mode of naturally occurring Ras effectors and acted as dominant-negative affinity reagents that block Ras signal transduction. Experiments with cancer cells showed that expression of these RBD variants inhibits Ras signaling, reducing cell growth and inducing apoptosis. Using these optimized RBD variants, we stratified patient-derived colorectal cancer organoids with known Ras mutational status according to their response to Ras inhibition. These results revealed that the presence of Ras mutations was insufficient to predict sensitivity to Ras inhibition, suggesting that not all of these tumors required Ras signaling for proliferation. In summary, by engineering the Ras/Raf interface of the CRAF-RBD, we identified potent and selective inhibitors of Ras in its active conformation that outcompete binding of Ras-signaling effectors.
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P. R. "Ras K-oncogen in and antigens on ovarian carcinoma cells." Medical Oncology and Tumor Pharmacotherapy 2, no. 1 (March 1985): 65. http://dx.doi.org/10.1007/bf02934796.
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Chippalkatti, Rohan, and Daniel Abankwa. "Promotion of cancer cell stemness by Ras." Biochemical Society Transactions 49, no. 1 (February 5, 2021): 467–76. http://dx.doi.org/10.1042/bst20200964.
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Cancer stem cells (CSC) may be the most relevant and elusive cancer cell population, as they have the exquisite ability to seed new tumors. It is plausible, that highly mutated cancer genes, such as KRAS, are functionally associated with processes contributing to the emergence of stemness traits. In this review, we will summarize the evidence for a stemness driving activity of oncogenic Ras. This activity appears to differ by Ras isoform, with the highly mutated KRAS having a particularly profound impact. Next to established stemness pathways such as Wnt and Hedgehog (Hh), the precise, cell cycle dependent orchestration of the MAPK-pathway appears to relay Ras activation in this context. We will examine how non-canonical activities of K-Ras4B (hereafter K-Ras) could be enabled by its trafficking chaperones calmodulin and PDE6D/PDEδ. Both dynamically localize to the cellular machinery that is intimately linked to cell fate decisions, such as the primary cilium and the centrosome. Thus, it can be speculated that oncogenic K-Ras disrupts fundamental polarized signaling and asymmetric apportioning processes that are necessary during cell differentiation.
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Wang, Xue-Qing, Howard Li, Vicki Van Putten, Robert A. Winn, Lynn E. Heasley, and Raphael A. Nemenoff. "Oncogenic K-Ras Regulates Proliferation and Cell Junctions in Lung Epithelial Cells through Induction of Cyclooxygenase-2 and Activation of Metalloproteinase-9." Molecular Biology of the Cell 20, no. 3 (February 2009): 791–800. http://dx.doi.org/10.1091/mbc.e08-07-0732.
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Expression of oncogenic K-Ras is frequently observed in non–small-cell lung cancer. However, oncogenic K-Ras is not sufficient to transform lung epithelial cells and requires collaborating signals that have not been defined. To examine the biological effects of K-Ras in nontransformed lung epithelial cells, stable transfectants were generated in RL-65 cells, a spontaneously immortalized lung epithelial cell line. Expression of K-Ras resulted in extracellular signal-regulated kinase (ERK) activation, which mediated induction of cyclooxygenase (COX)-2 and increased prostaglandin E2 production. Epithelial cells expressing oncogenic K-Ras showed increased proliferation in two- and three-dimensional tissue culture and delayed formation of hollow acinar structures in three-dimensional matrigel cultures. These affects were mediated through COX-2–dependent activation of β-catenin signaling and inhibition of apoptosis. ERK activation also led to induction of metalloproteinase (MMP)-9 and cleavage of E-cadherin at two specific sites. This resulted in partial disruption of adherens junctions as determined by decreased transepithelial resistance (TER), and disruption of E-cadherin/β-catenin interactions. An MMP-9 inhibitor reversed the decrease in TER and inhibited β-catenin signaling. These data indicate that although expression of oncogenic K-Ras does not transform lung epithelial cells, it alters the phenotype of the cells by increasing proliferation and decreasing cell–cell contacts characteristic of epithelial cells.
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Iwakura, Shinji, Yasutsugu Shirai, Tsunehiro Maeda, Toshiji Tominaga, Takayuki Nakase, Hiroyuki Tanishima, Satoru Tanaka, et al. "Two Case Reports of Resectable Cancer in the Remnant Pancreas after Pancreatectomy for Invasive Ductal Carcinoma of the Pancreas." International Surgery 103, no. 11-12 (November 1, 2019): 542–47. http://dx.doi.org/10.9738/intsurg-d-16-00182.1.
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Pancreatic cancer has an extremely poor prognosis. There are several reports on resectable cancer in the remnant pancreas after pancreatectomy; however, few have compared K-ras mutation patterns to clarify recurrent or second primary cancers. Here, we report on 2 cases of cancer in the remnant pancreas after total pancreatectomy for invasive ductal carcinoma. Case 1 is a 56-year-old man who underwent pancreaticoduodenectomy for cancer of the pancreatic head. However, serum carbohydrate antigen (CA19-9) was again elevated 23 months later. A tumor in the pancreatic tail was detected on abdominal computed tomography (CT), and total pancreatectomy was performed. Histologic examination of the tumors from both operations revealed moderately differentiated adenocarcinoma, and the surgical margins of both resected specimens were free of cancerous cells. The K-ras gene mutation was detected at codon 12V of exon 1 in both cancers. Case 2 is a 72-year-old woman who underwent distal pancreatectomy for cancer of the pancreatic body. However, serum CA19-9 was again elevated 4 years postoperatively. A tumor of the pancreatic head was detected on abdominal CT, and total pancreatectomy was performed. Histologic examination of the first and second tumors revealed poorly and moderately differentiated adenocarcinomas, respectively. The surgical margins of both resected specimens were free of cancerous cells. The K-ras gene mutation was detected at codon 12D of exon 1 in both cancers. These patients with rare pancreatic cancers both had metachronous carcinogenesis in the remnant pancreas.
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Stanslas, Johnson, Yuan Han Teh, Kok Lian Ho, Rajesh Ramasamy, and Sreenivasa Rao Sagineedu. "A K‐RAS Inhibitor Abrogates Self‐Renewal of Pancreatic Cancer Stem Cells via K‐RAS – NF‐κB – SOX2 Axis." FASEB Journal 34, S1 (April 2020): 1. http://dx.doi.org/10.1096/fasebj.2020.34.s1.02197.
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Boustanai, Ilana, Shiran Shapira, Dina Kazanov, and Nadir Arber. "Delivery of Bacterial Toxins Selectively Kills K-Ras Mutated Cancer Cells." American Journal of Gastroenterology 112 (October 2017): S105—S107. http://dx.doi.org/10.14309/00000434-201710001-00202.
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Mainardi, S., N. Mijimolle, S. Francoz, C. Vicente-Duenas, I. Sanchez-Garcia, and M. Barbacid. "Identification of cancer initiating cells in K-Ras driven lung adenocarcinoma." Proceedings of the National Academy of Sciences 111, no. 1 (December 23, 2013): 255–60. http://dx.doi.org/10.1073/pnas.1320383110.
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Xie, L., R. Lai, X. Wu, S. Zhang, X. Tang, and T. Chen. "Correlation between K-ras mutations status and benefit from cetuximab treatment in advanced colorectal cancer." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e15084-e15084. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e15084.
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e15084 Background: Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We follow -up study the efficacy and toxicity of cetuximab with chemotherapy in the treatment of advanced colorectal cancer from Chinese in East China. Methods: We analyzed tumor samples from 120 patients with advanced colorectal cancer by direct sequencing, to observe the mutations status in exon 2,3 of K-ras gene. And 30 patients were followed up according the RECIST standard for their treatment outcome of cetuximab plus chemotherapy at 2 -12 months. Results: K-ras mutations were identified in 48 of 120(40%) patients with colorectal cancer in exon2, which including 8 mutation types; 38/48(79.2%) mutations in 12 codon(G12D 43.7%,G12V 25%,G12C 10.4%,G12R 6%,G12S 4%,G12A 2%) and 10/48(18.7%) in 13 codon(G13D 18.7%,G13C 2%). None mutation was found in 61codon of exon3. we observed the clinical efficacy of 30 patients treated by cetuximab plus chemotherapy, of 21 patients with wild-type K-ras tumors as compared with 9 patients with mutated K-ras significantly improved the response rate (5/21 21.8% vs 1/9 11.1%,P<0.01)and the disease control rate (19/21 90.4% vs,2/9 22.2%,P<0.01). There were a few patients with mutated K-ras tumors benefit from cetuximab, in which the fluorescence intensity of mutation cells of all detected tumor tissue approach to 1:3 status by sequencing analysis. The major toxicities of treatment were acne-like rash, which were found in 14/21(66.6%)of patients with wild-type K- ras, and 5/9(55.5%)of patients with mutated K-ras . Conclusions: The East-China patients share the same (40%) mutation frequency and type of k-ras gene with other races . Patients with wild type K-ras mutation have significantly higher Response rate and disease control rate on cetuximab plus chemotherapy treatment .Our results once again show that somatic mutations status of k-ras is a major determinant of cetuximab response in advanced colorectal cancer. There was no statistical correlation between acne-like rash of the major toxicities and mutations status of k-ras. There were a few patients bearing mutated k-ras did benefit from cetuximab, that would need to be validation between Chinese or Ethnicity association phenotype by a large numbers of samples. No significant financial relationships to disclose.
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Liang, Hong, Huanwen Mu, Frantz Jean-Francois, Bindu Lakshman, Suparna Sarkar-Banerjee, Yinyin Zhuang, Yongpeng Zeng, et al. "Membrane curvature sensing of the lipid-anchored K-Ras small GTPase." Life Science Alliance 2, no. 4 (July 11, 2019): e201900343. http://dx.doi.org/10.26508/lsa.201900343.
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Plasma membrane (PM) curvature defines cell shape and intracellular organelle morphologies and is a fundamental cell property. Growth/proliferation is more stimulated in flatter cells than the same cells in elongated shapes. PM-anchored K-Ras small GTPase regulates cell growth/proliferation and plays key roles in cancer. The lipid-anchored K-Ras form nanoclusters selectively enriched with specific phospholipids, such as phosphatidylserine (PS), for efficient effector recruitment and activation. K-Ras function may, thus, be sensitive to changing lipid distribution at membranes with different curvatures. Here, we used complementary methods to manipulate membrane curvature of intact/live cells, native PM blebs, and synthetic liposomes. We show that the spatiotemporal organization and signaling of an oncogenic mutant K-RasG12V favor flatter membranes with low curvature. Our findings are consistent with the more stimulated growth/proliferation in flatter cells. Depletion of endogenous PS abolishes K-RasG12V PM curvature sensing. In cells and synthetic bilayers, only mixed-chain PS species, but not other PS species tested, mediate K-RasG12V membrane curvature sensing. Thus, K-Ras nanoclusters act as relay stations to convert mechanical perturbations to mitogenic signaling.
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Brenner, D. E., Y. Su, D. P. Normolle, S. Syngal, R. Bresalier, N. Marcon, J. Baron, and T. Block. "Detection of colorectal neoplasia associated K-Ras mutations in human urine." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 1005. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.1005.
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1005 Background: Since colorectal neoplasia-associated genes have been detected in human blood, we hypothesized that small DNA fragments containing genetic mutations associated with colorectal neoplasias are filtered and excreted in the urine. If so, genes associated with colorectal cancer will be detected in the urine. K-ras mutations are commonly associated with colorectal neoplasia and do not occur in the urinary tract. Methods: K-ras mutation detection: 200 microl of urine was extracted with guanidine thiocyanate and purifed using a Wizard DNA isolation kit. Codon 12 K-ras mutation detection methods–1: restriction enriched PCR, 20 cycles, with primers that amplify both wild type and mutated DNA but with an artificial BstNI site at the 5’ end of the amplified product (>2 K-ras copies per assay); 2: Peptide nucleic acid clamping real time PCR (>15 K-ras copies per assay). Human subjects: Training set = 20 patients with known K-ras mutations in colorectal cancer tissue. Test set = blinded urine samples from colorectal adenocarcinoma (N=48), adenoma (N=31), hyperplastic polyp (N=12) and endoscopically normal colon and rectum (N=60). Results: 1. Human urine contains 150–250 base pair DNA fragments derived from the circulation. These fragments can be readily distinguished from high molecular weight DNA from sloughed urinary tract cells. 2. Training set for K-ras detection (tissue confirmed K-ras mutations): Serum 6/20 (30%), Plasma (11/20 (55%), Urine: 18/20 (90%), (p<0.15 for plasma, p<0.001 for serum). 3. Test set (blinded): a. >2 copies of mutated K-ras genes were detected in: 16/48 (33%) adenocarcinomas; 23/31 (74%) adenomas; 5/12 (42%) hyperplastic polyps, and 19/60 (31%) non-neoplasia controls. b. >15 copies of mutated K-ras genes were detected in: 12/48 (25%) adenocarinomas; 15/31 (48%) adenomas; 3/12 (25%) hyperplastic polyps, and 11/60 (18%) non-neoplasia controls. Conclusions: Small DNA fragments in human urine contain K-Ras mutations identical to those found in colorectal cancer DNA. The sensitivity for detection of K-ras mutations in urine appears equivalent or superior to K-ras mutation detection in feces or serum. DNA mutations from systemic epithelial neoplasias may be detected in filtered urinary DNA fragments and may be useful for early detection of neoplasia. No significant financial relationships to disclose.