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Pehlivan, Melek, Ceyda Caliskan, Zeynep Yuce, and Hakkı Ogun Sercan. "Forced expression of Wnt antagonists sFRP1 and WIF1 sensitizes chronic myeloid leukemia cells to tyrosine kinase inhibitors." Tumor Biology 39, no. 5 (May 2017): 101042831770165. http://dx.doi.org/10.1177/1010428317701654.
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Chronic myeloid leukemia is a clonal myeloproliferative disorder that arises from the neoplastic transformation of the hematopoietic stem cell, in which the Wnt/β-catenin signaling pathway has been demonstrated to play an important role in disease progression. However, the role of Wnt signaling antagonists in therapy resistance and disease progression has not been fully investigated. We aimed to study the effects of Wnt/β-catenin pathway antagonists—secreted frizzled-related protein 1 and Wnt inhibitory factor 1—on resistance toward tyrosine kinase inhibitors in chronic myeloid leukemia. Response to tyrosine kinase inhibitors was analyzed in secreted frizzled-related protein 1 and Wnt inhibitory factor 1 stably transfected K562 cells. Experiments were repeated using a tetracycline-inducible expression system, confirming previous results. In addition, response to tyrosine kinase inhibitor treatment was also analyzed using the secreted frizzled-related protein 1 expressing, BCR-ABL positive MEG01 cell line, in the presence and absence of a secreted frizzled-related protein 1 inhibitor. Our data suggests that total cellular β-catenin levels decrease in the presence of secreted frizzled-related protein 1 and Wnt inhibitory factor 1, and a significant increase in cell death after tyrosine kinase inhibitor treatment is observed. On the contrary, when secreted frizzled-related protein 1 is suppressed, total β-catenin levels increase in the cell and the cells become resistant to tyrosine kinase inhibitors. We suggest that Wnt antagonists carry the potential to be exploited in designing new agents and strategies for the advanced and resistant forms of chronic myeloid leukemia.
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Watanabe, K., and X. Dai. "Winning WNT: Race to Wnt signaling inhibitors." Proceedings of the National Academy of Sciences 108, no. 15 (March 30, 2011): 5929–30. http://dx.doi.org/10.1073/pnas.1103102108.
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Rogaczewski, Patryk, Michał Janiak, Kamil Borysewicz, Tadeusz Głos, Navid Ahmadi, and Łukasz Szylberg. "Clinical significancy of WNT pathway inhibition in various cancers." Journal of Education, Health and Sport 12, no. 11 (November 3, 2022): 183–91. http://dx.doi.org/10.12775/jehs.2022.12.11.024.
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The tumor microenvironment (TME) plays an important role in the cell cycle. There is a correlation between the Wnt/B–catenin signaling pathway and TME. This article reviews methods of inhibiting Wnt Pathway, a useful process in the treatment of various cancers. Compounds of Wnt/β–Catenin Signaling Pathway, such as TCF–1, have an impact on the differentiation and migration of CD8+ T cells. CCL4 expression is regulated by the beta–catenin protein to recruit CD103+ dendritic cells, which enables CD8+ T cell activation. Inhibition of the Wnt/β–catenin pathway has an impact on ovarian cancer patients’ prognosis, reducing the development of ovarian cancer. Research shows that inhibition of the pathway with the use of the LGK974 inhibitor may boost immunity, especially when applied with a Paclitaxel mix. After treatment, expression of the inhibitory receptors CTLA–4, TIM3, PD–1 on CD8+ T cells decreased. The combination of LGK974 and Paclitaxel can cause the death of tumor cells and significantly inhibit their proliferation. The application of dose–dense Paclitaxel avoids toxicity related to the maximum dose needed to protect the patient's immune system by increasing CD8+ TILs. There are concerns regarding toxicity of the LGK 974, especially for cells dependent on the Wnt/β–catenin pathway to maintain homeostasis. Many Wnt/β–catenin pathway inhibitors are tested against colorectal cancer (CRC) with successful results. These include NSAIDs, porcupine inhibitors, tankyrase inhibitors, Wnt5A inhibitors, and disheveled protein inhibitors.The Wnt/β–catenin pathway, when expressed in Triple Negative Breast Cancer (TNBC), leads to the transition of epithelial to mesenchymal cells. In early clinical development, there are multiple inhibitors (ex. KYA1797K) targeting the Wnt/β–catenin pathway in TNBC cells, which could become a viable anticancer strategy.
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Griffiths, Elizabeth A., Craig M. Hooker, Michael A. McDevitt, Judith E. Karp, James G. Herman, and Hetty E. Carraway. "Acute Myeloid Leukemia Is Characterized by Wnt Pathway Inhibitor Promoter Methylation." Blood 112, no. 11 (November 16, 2008): 2253. http://dx.doi.org/10.1182/blood.v112.11.2253.2253.
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Abstract The Wnt pathway contributes to a stem-cell like phenotype in a variety of cancer subtypes. Nuclear localization of non-phosphorylated, active β-catenin is a surrogate marker for Wnt pathway activation and has been associated with adverse outcome in patients with acute myeloid leukemia (AML). Wnt pathway inhibitors including APC, DKK1, DKK3, LKB1/STK11, RASSF1A, RUNX3, SFRP1, SFRP2, SFRP4, SFRP5, SOX17, and WIF1 contain extensive promoter region CpG islands. Wnt pathway inhibitors are silenced by promoter methylation in many malignancies including lung cancer, colon cancer and acute lymphoid leukemias. To determine if methylation of these Wnt pathway inhibitors is present in AML, we evaluated leukemia cell lines (i.e., K562, HNT34, KG1, KG1A, U937, and HL60) for evidence of promoter methylation. Additionally, 188 AML patient (median age 61 years) samples from the Johns Hopkins Hospital leukemia tumor bank were assessed for the presence of Wnt pathway inhibitor methylation. All samples were bisulfite treated and evaluated for promoter methylation using methylation specific PCR. Diagnostic samples from a subgroup of patients with normal cytogenetics (n=73) who received high dose induction therapy were evaluated for potential associations between methylation of individual Wnt pathway inhibitor genes or total number of methylated genes and event free or overall survival. RESULTS: Extensive promoter methylation of the Wnt pathway inhibitor genes was observed in leukemia cell lines. Of the primary leukemia samples, 85% had at least one methylated gene. Promoter methylation of Wnt inhibitors was common in these samples with the following frequencies: DKK1 (16%;30/188), DKK3 (8%;15/188), RUNX3 (27%;50/188), SFRP1 (34%;63/188), SFRP2 (66%;124/188), SFRP4 (9%;16/188), SFRP5 (54%;102/188), SOX17 (29%;54/188), and WIF1 (32%;61/188). This is among the first comprehensive evaluations of Wnt pathway inhibitor methylation in primary samples from AML patients. The frequency of methylation seen here is comparable to that observed in established tumor suppressor genes in patients with AML, including p15INK4B, SOCS1 and CDH1. In marked contrast with epithelial tumors, methylation of APC (2%;2/108) and RASSF1A (0%;0/188) was rare. LKB1/STK11 methylation was also uncommon (2%;2/108). Previous reports have associated Wnt pathway activation with poor prognosis. In our treated patients with normal cytogenetics, no correlation was observed between methylation of Wnt pathway inhibitors and event free or overall survival. In conclusion, in patients with AML (a) there is a high frequency of Wnt pathway inhibitor methylation; (b) Wnt pathway inhibitor methylation is distinct from that observed in epithelial malignancies; and (c) methylation of Wnt pathway genes does not correlate with adverse clinical outcome.
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Filipovich, Alexandra, Iris Gehrke, Simon J. Poll-Wolbeck, and Karl-Anton Kreuzer. "Physiological inhibitors of Wnt signaling." European Journal of Haematology 86, no. 6 (May 17, 2011): 453–65. http://dx.doi.org/10.1111/j.1600-0609.2011.01592.x.
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Román-Gómez, José, Lucia Cordeu, Xabier Agirre, Antonio Jiménez-Velasco, Edurne San José-Eneriz, Leire Garate, María José Calasanz, Anabel Heiniger, Antonio Torres, and Felipe Prosper. "Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia." Blood 109, no. 8 (December 5, 2006): 3462–69. http://dx.doi.org/10.1182/blood-2006-09-047043.
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Abstract Activation of the Wnt/β-catenin signaling pathway is a hallmark of a number of solid tumors. We analyzed the regulation of the Wnt/β-catenin pathway in acute lymphoblastic leukemia (ALL) and its role in the pathogenesis of the disease. We found that expression of the Wnt inhibitors sFRP1, sFRP2, sFRP4, sFRP5, WIF1, Dkk3, and Hdpr1 was down-regulated due to abnormal promoter methylation in ALL cell lines and samples from patients with ALL. Methylation of Wnt inhibitors was associated with activation of the Wnt-signaling pathway as demonstrated by the up-regulation of the Wnt target genes WNT16, FZ3, TCF1, LEF1, and cyclin D1 in cell lines and samples and the nuclear localization of β-catenin in cell lines. Treatment of ALL cells with the Wnt inhibitor quercetin or with the demethylating agent 5-aza-2′-deoxycytidine induced an inactivation of the Wnt pathway and induced apoptosis of ALL cells. Finally, in a group of 261 patients with newly diagnosed ALL, abnormal methylation of Wnt inhibitors was associated with decreased 10-year disease-free survival (25% versus 66% respectively, P < .001) and overall survival (28% versus 61% respectively, P = .001). Our results indicate a role of abnormal Wnt signaling in ALL and establish a group of patients with a significantly worse prognosis (methylated group).
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Elyamany, Ghaleb, Hassan Rizwan, Ariz Akhter, Mansour S. Aljabry, Sultan Alotaibi, Mohammad A. Hameed Albalawi, Meer-Taher Shabani-Rad, Tariq Mahmood Roshan, and Adnan Mansoor. "“Losing the Brakes”—Suppressed Inhibitors Triggering Uncontrolled Wnt/ß-Catenin Signaling May Provide a Potential Therapeutic Target in Elderly Acute Myeloid Leukemia." Current Issues in Molecular Biology 45, no. 1 (January 9, 2023): 604–13. http://dx.doi.org/10.3390/cimb45010040.
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Dysregulated Wnt/β-catenin signal transduction is implicated in initiation, propagation, and poor prognosis in AML. Epigenetic inactivation is central to Wnt/β-catenin hyperactivity, and Wnt/β-catenin inhibitors are being investigated as targeted therapy. Dysregulated Wnt/β-catenin signaling has also been linked to accelerated aging. Since AML is a disease of old age (>60 yrs), we hypothesized age-related differential activity of Wnt/β-catenin signaling in AML patients. We probed Wnt/β-catenin expression in a series of AML in the elderly (>60 yrs) and compared it to a cohort of pediatric AML (<18 yrs). RNA from diagnostic bone marrow biopsies (n = 101) were evaluated for key Wnt/β-catenin molecule expression utilizing the NanoString platform. Differential expression of significance was defined as >2.5-fold difference (p < 0.01). A total of 36 pediatric AML (<18 yrs) and 36 elderly AML (>60 yrs) were identified in this cohort. Normal bone marrows (n = 10) were employed as controls. Wnt/β-catenin target genes (MYC, MYB, and RUNX1) showed upregulation, while Wnt/β-catenin inhibitors (CXXR, DKK1-4, SFRP1-4, SOST, and WIFI) were suppressed in elderly AML compared to pediatric AML and controls. Our data denote that suppressed inhibitor expression (through mutation or hypermethylation) is an additional contributing factor in Wnt/β-catenin hyperactivity in elderly AML, thus supporting Wnt/β-catenin inhibitors as potential targeted therapy.
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Li, Bo, Jinxia Liang, Feng Lu, Guandi Zeng, Jindao Zhang, Yinxing Ma, Peng Liu, Qin Wang, Qian Zhou, and Liang Chen. "Discovery of Novel Inhibitor for WNT/β-Catenin Pathway by Tankyrase 1/2 Structure-Based Virtual Screening." Molecules 25, no. 7 (April 6, 2020): 1680. http://dx.doi.org/10.3390/molecules25071680.
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Aberrant activation of the WNT/β-catenin signaling pathway is implicated in various types of cancers. Inhibitors targeting the Wnt signaling pathway are intensively studied in the current cancer research field, the outcomes of which remain to be determined. In this study, we have attempted to discover novel potent WNT/β-catenin pathway inhibitors through tankyrase 1/2 structure-based virtual screening. After screening more than 13.4 million compounds through molecular docking, we experimentally verified one compound, LZZ-02, as the most potent inhibitor out of 11 structurally representative top hits. LiCl-induced HEK293 cells containing TOPFlash reporter showed that LZZ-02 inhibited the transcriptional activity of β-catenin with an IC50 of 10 ± 1.2 μM. Mechanistically, LZZ-02 degrades the expression of β-catenin by stabilizing axin 2, thereby diminishing downstream proteins levels, including c-Myc and cyclin D1. LZZ-02 also inhibits the growth of colonic carcinoma cell harboring constitutively active β-catenin. More importantly, LZZ-02 effectively shrinks tumor xenograft derived from colonic cell lines. Our study successfully identified a novel tankyrase 1/2 inhibitor and shed light on a novel strategy for developing inhibitors targeting the WNT/β-catenin signaling axis.
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Ye, Zhen-Nan, Feng Yuan, Jie-Qing Liu, Xing-Rong Peng, Tao An, Xue Li, Ling-Mei Kong, Ming-Hua Qiu, and Yan Li. "Physalis peruviana-Derived 4β-Hydroxywithanolide E, a Novel Antagonist of Wnt Signaling, Inhibits Colorectal Cancer In Vitro and In Vivo." Molecules 24, no. 6 (March 22, 2019): 1146. http://dx.doi.org/10.3390/molecules24061146.
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Deregulation of the Wnt signaling pathway leads to colorectal cancer progression. Natural dietary compounds serve as promising candidates for development as chemopreventive agents by suppressing the Wnt/β-catenin signaling pathway. Physalis peruviana-derived 4βHWE showed a significant inhibitory activity with a calculated IC50 of 0.09 μΜ in a screening of novel inhibitors of Wnt signaling with the dual-luciferase reporter assay. This study investigated the anti-tumor effect of 4βHWE and the potential Wnt signaling inhibitory mechanism. Both the western blot analysis and immunofluorescence assay showed that 4βHWE promoted the phosphorylation and degradation of β-catenin and the subsequent inhibition of its nuclear translocation to attenuate the endogenous Wnt target gene expression in colorectal cancer (CRC) cells. The cell viability assay indicated that 4βHWE preferentially inhibited the proliferation of CRC compared with CCD-841-CoN, a normal human colonic epithelial cell line. 4βHWE-mediated G0/G1 cell cycle arrest and apoptosis induction contributed to the suppression of the proliferation of CRC in the cell cycle and Annexin V-FITC/Propidium Iodide apoptosis analysis. Moreover, in vivo, 4βHWE dramatically inhibited tumor growth in HCT116 xenografts by attenuating the Wnt/β-catenin signaling pathway. In conclusion, our study suggested that 4βHWE could be of potential use in anti-tumor agent development as a novel Wnt signaling inhibitor.
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Mii, Yusuke, and Masanori Taira. "Secreted Wnt “inhibitors” are not just inhibitors: Regulation of extracellular Wnt by secreted Frizzled-related proteins." Development, Growth & Differentiation 53, no. 8 (October 2011): 911–23. http://dx.doi.org/10.1111/j.1440-169x.2011.01299.x.
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Xiao, Yao, Thiago F. Amaral, Pablo J. Ross, Delia A. Soto, Kenneth E. Diffenderfer, Aimee R. Pankonin, Surawich Jeensuk, Paula Tríbulo, and Peter J. Hansen. "Importance of WNT-dependent signaling for derivation and maintenance of primed pluripotent bovine embryonic stem cells." Biology of Reproduction 105, no. 1 (April 23, 2021): 52–63. http://dx.doi.org/10.1093/biolre/ioab075.
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Abstract The WNT signaling system plays an important but paradoxical role in the regulation of pluripotency. In the cow, IWR-1, which inhibits canonical WNT activation and has WNT-independent actions, promotes the derivation of primed pluripotent embryonic stem cells from the blastocyst. Here, we describe a series of experiments to determine whether derivation of embryonic stem cells could be generated by replacing IWR-1 with other inhibitors of WNT signaling. Results confirm the importance of inhibition of canonical WNT signaling for the establishment of pluripotent embryonic stem cells in cattle and indicate that the actions of IWR-1 can be mimicked by the WNT secretion inhibitor IWP2 but not by the tankyrase inhibitor XAV939 or WNT inhibitory protein dickkopf 1. The role of Janus kinase-mediated signaling pathways for the maintenance of pluripotency of embryonic stem cells was also evaluated. Maintenance of pluripotency of embryonic stem cells lines was blocked by a broad inhibitor of Janus kinase, even though the cells did not express phosphorylated signal transducer and activator of transcription 3 (pSTAT3). Further studies with blastocysts indicated that IWR-1 blocks the activation of pSTAT3. A likely explanation is that IWR-1 blocks differentiation of embryonic stem cells into a pSTAT3+ lineage. In conclusion, results presented here indicate the importance of inhibition of WNT signaling for the derivation of pluripotent bovine embryonic stem cells, the role of Janus kinase signaling for maintenance of pluripotency, and the participation of IWR-1 in the inhibition of activation of STAT3.
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Zhong, Yu, Paula Katavolos, Trung Nguyen, Ted Lau, Jason Boggs, Amy Sambrone, David Kan, et al. "Tankyrase Inhibition Causes Reversible Intestinal Toxicity in Mice with a Therapeutic Index < 1." Toxicologic Pathology 44, no. 2 (December 20, 2015): 267–78. http://dx.doi.org/10.1177/0192623315621192.
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Activated Wnt/β-catenin signaling is frequently associated with colorectal cancer. Wnt inhibitors, including tankyrase inhibitors, are being explored as potential anticancer agents. Wnt signaling is also critical for intestinal tissue homeostasis, and Wnt inhibitors have been shown to cause intestinal toxicity in mice by affecting intestinal stem cells. This study sought to characterize the intestinal toxicity of tankyrase inhibitors, including reversibility, and to assess their therapeutic index. Novel tankyrase inhibitor G-631 caused dose-dependent intestinal toxicity with a therapeutic index < 1 after 14 days of dosing in mice. At a tolerated subtherapeutic dose level, the intestinal toxicity was composed of enteritis characterized by villus blunting, epithelial degeneration, and inflammation, which fully reversed after 14 days of recovery. Doubled exposure showed weak antitumor activity in a xenograft colorectal cancer model but also caused more severe intestinal toxicity characterized by multifocal-regionally extensive necrotizing and ulcerative enteritis leading to morbidity or moribundity in some animals. This toxicity was only partially reversed after 14 days of recovery, with evidence of crypt and villus regeneration, mildly blunted villi, and/or scarring in association with chronic inflammation of the submucosa. Therefore, the clinical utility of tankyrase inhibitors is likely limited by the on-target intestinal toxicity and a therapeutic index < 1 in mice.
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Zhao, Yuanyuan, Leilei Tao, Jun Yi, Haizhu Song, and Longbang Chen. "The Role of Canonical Wnt Signaling in Regulating Radioresistance." Cellular Physiology and Biochemistry 48, no. 2 (2018): 419–32. http://dx.doi.org/10.1159/000491774.
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Radioresistance is a major obstacle in radiotherapy for cancer, and strategies are needed to overcome this problem. Currently, radiotherapy combined with targeted therapy such as inhibitors of phosphoinosotide 3-kinase/Akt and epidermal growth factor receptor signaling have become the focus of studies on radiosensitization. Apart from these two signaling pathways, which promote radioresistance, deregulation of Wnt signaling is also associated with the radioresistance of multiple cancers. Wnts, as important messengers in the tumor microenvironment, are involved in cancer progression mainly via canonical Wnt signaling. Their role in promoting DNA damage repair and inhibiting apoptosis facilitates cancer resistance to radiation. Thus, it seems reasonable to target Wnt signaling as a method for overcoming radioresistance. Many small-molecule inhibitors that target the Wnt signaling pathway have been identified and shown to promote radiosensitization. Therefore, a Wnt signaling inhibitor may help to overcome radioresistance in cancer therapy.
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Chang, Chun-Chun, Sheng-Feng Pan, Min-Huang Wu, Chun-Tse Cheng, Yan-Rui Su, Shinn-Jong Jiang, and Hao-Jen Hsu. "Combinatorial Virtual Screening Revealed a Novel Scaffold for TNKS Inhibition to Combat Colorectal Cancer." Biomedicines 10, no. 1 (January 10, 2022): 143. http://dx.doi.org/10.3390/biomedicines10010143.
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The abnormal Wnt signaling pathway leads to a high expression of β-catenin, which causes several types of cancer, particularly colorectal cancer (CRC). The inhibition of tankyrase (TNKS) activity can reduce cancer cell growth, invasion, and resistance to treatment by blocking the Wnt signaling pathway. A pharmacophore search and pharmacophore docking were performed to identify potential TNKS inhibitors in the training databases. The weighted MM/PBSA binding free energy of the docking model was calculated to rank the databases. The reranked results indicated that 26.98% of TNKS inhibitors that were present in the top 5% of compounds in the database and near an ideal value ranked 28.57%. The National Cancer Institute database was selected for formal virtual screening, and 11 potential TNKS inhibitors were identified. An enzyme-based experiment was performed to demonstrate that of the 11 potential TNKS inhibitors, NSC295092 and NSC319963 had the most potential. Finally, Wnt pathway analysis was performed through a cell-based assay, which indicated that NSC319963 is the most likely TNKS inhibitor (pIC50 = 5.59). The antiproliferation assay demonstrated that NSC319963 can decrease colorectal cancer cell growth; therefore, the proposed method successfully identified a novel TNKS inhibitor that can alleviate CRC.
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Kim, Yonghyo, Myoung-Hee Kang, and Yong-Hee Cho. "API-2-Induced Cell Migration Is Overcome by Small Molecular Approaches Inhibiting β-Catenin." Current Issues in Molecular Biology 44, no. 12 (November 29, 2022): 6006–14. http://dx.doi.org/10.3390/cimb44120409.
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Frequent mutation of APC (90%) in advanced colorectal cancer (CRC) results in the simultaneous activation of Wnt/β-catenin and AKT signaling pathways, and the current therapeutic limitations of the AKT inhibitors for treating CRC patients are nuclear β-catenin-induced EMT and bypassing apoptosis. In this study, we discover that the combinatorial treatment of an AKT inhibitor and KY1022, a β-catenin destabilizer, effectively overcomes the current limitations of API-2, an AKT inhibitor, by reducing nuclear β-catenin. Taken together, we demonstrate that the simultaneous suppression of Wnt/β-catenin with the AKT signaling pathways is an ideal strategy for suppressing the AKT-inhibitor-mediated metastasis and for maximizing the therapeutic effects of AKT inhibitors.
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Hao, Jing, Xiangzi Han, Haidong Huang, xingjiang yu, Shideng Bao, Richard Prayson, and Jennifer Yu. "DDRE-15. Sema3C SIGNALING CONFERS RESISTANCE TO Wnt INHIBITION IN GLIOBLASTOMA." Neuro-Oncology 23, Supplement_6 (November 2, 2021): vi77. http://dx.doi.org/10.1093/neuonc/noab196.299.
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Abstract BACKGROUND Wnt signaling is widely dysregulated in cancer. The therapeutic potential of Wnt inhibitors appears promising in preclinical studies. However, they have uniformly failed clinical trials. How cancer cells develop Wnt inhibitor resistance is poorly understood. Current Wnt inhibitors are designed targeting either ligand or receptor. We hypothesized cancer cells will bypass ligand-receptor interaction through an unknown mechanism. We focused on the neurodevelopmental signaling program of Semaphorin 3C (Sema3C) that is upregulated in 85% of GBM and regulates glioma stem-cell-driven tumor progression. RESULTS Porcupine inhibitor LGK974 reduced TCF1 expression in the GBM tumor mouse models, suggesting successful target engagement in vivo. However, it failed to prolong the overall survival. Sema3C expression strongly correlated with TCF1 expression in human GBM samples by immunohistochemical analysis. Genetic inhibition of Sema3C and TCF1 together prolonged animal survival more than either alone, indicating better control of Wnt pathway signaling with dual pathway blockade. Immunofluorescence and cell fractionation studies revealed that Sema3C signaling drove β-catenin nuclear accumulation. Sema3C regulates transactivation of Wnt target genes including TCF1, c-Myc and c-Met. Sema3C pathway activates Rac1. It is reported that Rac1 activates β-catenin and promotes β-catenin nuclear accumulation. In GSCs, constitutively active Rac1 restored β-catenin nuclear localization and rescued TCF1 and c-Myc down-regulation in the setting of Sema3C silencing. Sema3C can drive canonical Wnt signaling even when Wnt ligand secretion is blocked. Together, the data support that GSCs can escape Wnt inhibition through Sema3C and Rac1. CONCLUSIONS Sema3C signaling drives canonical Wnt signaling, providing an escape mechanism for cancer cells despite Wnt ligand-receptor interruption. Sema3C-β-catenin signaling promotes GSC self-renewal and tumor progression. Upstream Wnt pathway inhibition alone is insufficient to control tumors. Our data provide a therapeutic strategy of dual blockade of Wnt and Sema3C pathways to provide clinically significant tumor control.
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Predes, Danilo, Luiz F. S. Oliveira, Laís S. S. Ferreira, Lorena A. Maia, João M. A. Delou, Anderson Faletti, Igor Oliveira, et al. "The Chalcone Lonchocarpin Inhibits Wnt/β-Catenin Signaling and Suppresses Colorectal Cancer Proliferation." Cancers 11, no. 12 (December 7, 2019): 1968. http://dx.doi.org/10.3390/cancers11121968.
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The deregulation of the Wnt/β-catenin signaling pathway is a central event in colorectal cancer progression, thus a promising target for drug development. Many natural compounds, such as flavonoids, have been described as Wnt/β-catenin inhibitors and consequently modulate important biological processes like inflammation, redox balance, cancer promotion and progress, as well as cancer cell death. In this context, we identified the chalcone lonchocarpin isolated from Lonchocarpus sericeus as a Wnt/β-catenin pathway inhibitor, both in vitro and in vivo. Lonchocarpin impairs β-catenin nuclear localization and also inhibits the constitutively active form of TCF4, dnTCF4-VP16. Xenopus laevis embryology assays suggest that lonchocarpin acts at the transcriptional level. Additionally, we described lonchocarpin inhibitory effects on cell migration and cell proliferation on HCT116, SW480, and DLD-1 colorectal cancer cell lines, without any detectable effects on the non-tumoral intestinal cell line IEC-6. Moreover, lonchocarpin reduces tumor proliferation on the colorectal cancer AOM/DSS mice model. Taken together, our results support lonchocarpin as a novel Wnt/β-catenin inhibitor compound that impairs colorectal cancer cell growth in vitro and in vivo.
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Kazanskaya, O., A. Glinka, and C. Niehrs. "The role of Xenopus dickkopf1 in prechordal plate specification and neural patterning." Development 127, no. 22 (November 15, 2000): 4981–92. http://dx.doi.org/10.1242/dev.127.22.4981.
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Dickkopf1 (dkk1) encodes a secreted WNT inhibitor expressed in Spemann's organizer, which has been implicated in head induction in Xenopus. Here we have analyzed the role of dkk1 in endomesoderm specification and neural patterning by gain- and loss-of-function approaches. We find that dkk1, unlike other WNT inhibitors, is able to induce functional prechordal plate, which explains its ability to induce secondary heads with bilateral eyes. This may be due to differential WNT inhibition since dkk1, unlike frzb, inhibits Wnt3a signalling. Injection of inhibitory antiDkk1 antibodies reveals that dkk1 is not only sufficient but also required for prechordal plate formation but not for notochord formation. In the neural plate dkk1 is required for anteroposterior and dorsoventral patterning between mes- and telencephalon, where dkk1 promotes anterior and ventral fates. Both the requirement of anterior explants for dkk1 function and their ability to respond to dkk1 terminate at late gastrula stage. Xenopus embryos posteriorized with bFGF, BMP4 and Smads are rescued by dkk1. dkk1 does not interfere with the ability of bFGF to induce its immediate early target gene Xbra, indicating that its effect is indirect. In contrast, there is cross-talk between BMP and WNT signalling, since induction of BMP target genes is sensitive to WNT inhibitors until the early gastrula stage. Embryos treated with retinoic acid (RA) are not rescued by dkk1 and RA affects the central nervous system (CNS) more posterior than dkk1, suggesting that WNTs and retinoids may act to pattern anterior and posterior CNS, respectively, during gastrulation.
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Thorne, Curtis A., Bonnie Lafleur, Michelle Lewis, Alison J. Hanson, Kristin K. Jernigan, David C. Weaver, Kari A. Huppert, et al. "A Biochemical Screen for Identification of Small-Molecule Regulators of the Wnt Pathway Using Xenopus Egg Extracts." Journal of Biomolecular Screening 16, no. 9 (August 21, 2011): 995–1006. http://dx.doi.org/10.1177/1087057111416657.
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Misregulation of the Wnt pathway has been shown to be responsible for a variety of human diseases, most notably cancers. Screens for inhibitors of this pathway have been performed almost exclusively using cultured mammalian cells or with purified proteins. We have previously developed a biochemical assay using Xenopus egg extracts to recapitulate key cytoplasmic events in the Wnt pathway. Using this biochemical system, we show that a recombinant form of the Wnt coreceptor, LRP6, regulates the stability of two key components of the Wnt pathway (β-catenin and Axin) in opposing fashion. We have now fused β-catenin and Axin to firefly and Renilla luciferase, respectively, and demonstrate that the fusion proteins behave similarly as their wild-type counterparts. Using this dual luciferase readout, we adapted the Xenopus extracts system for high-throughput screening. Results from these screens demonstrate signal distribution curves that reflect the complexity of the library screened. Of several compounds identified as cytoplasmic modulators of the Wnt pathway, one was further validated as a bona fide inhibitor of the Wnt pathway in cultured mammalian cells and Xenopus embryos. We show that other embryonic pathways may be amendable to screening for inhibitors/modulators in Xenopus egg extracts.
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Kulak, Ozlem, Hua Chen, Brody Holohan, Xiaofeng Wu, Huawei He, Dominika Borek, Zbyszek Otwinowski, et al. "Disruption of Wnt/β-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human Cells." Molecular and Cellular Biology 35, no. 14 (May 4, 2015): 2425–35. http://dx.doi.org/10.1128/mcb.00392-15.
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Maintenance of chromosomal ends (telomeres) directly contributes to cancer cell immortalization. The telomere protection enzymes belonging to the tankyrase (Tnks) subfamily of poly(ADP-ribose) polymerases (PARPs) have recently been shown to also control transcriptional response to secreted Wnt signaling molecules. Whereas Tnks inhibitors are currently being developed as therapeutic agents for targeting Wnt-related cancers and as modulators of Wnt signaling in tissue-engineering agendas, their impact on telomere length maintenance remains unclear. Here, we leveraged a collection of Wnt pathway inhibitors with previously unassigned mechanisms of action to identify novel pharmacophores supporting Tnks inhibition. A multifaceted experimental approach that included structural, biochemical, and cell biological analyses revealed two distinct chemotypes with selectivity for Tnks enzymes. Using these reagents, we revealed that Tnks inhibition rapidly induces DNA damage at telomeres and telomeric shortening upon long-term chemical exposure in cultured cells. On the other hand, inhibitors of the Wnt acyltransferase Porcupine (Porcn) elicited neither effect. Thus, Tnks inhibitors impact telomere length maintenance independently of their affects on Wnt/β-catenin signaling. We discuss the implications of these findings for anticancer and regenerative medicine agendas dependent upon chemical inhibitors of Wnt/β-catenin signaling.
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Ma, Fen, Seiji Arai, Keshan Wang, Carla Calagua, Amanda R. Yuan, Larysa Poluben, Zhongkai Gu, et al. "Autocrine Canonical Wnt Signaling Primes Noncanonical Signaling through ROR1 in Metastatic Castration-Resistant Prostate Cancer." Cancer Research 82, no. 8 (February 7, 2022): 1518–33. http://dx.doi.org/10.1158/0008-5472.can-21-1807.
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Abstract Wnt signaling driven by genomic alterations in genes including APC and CTNNB, which encodes β-catenin, have been implicated in prostate cancer development and progression to metastatic castration-resistant prostate cancer (mCRPC). However, nongenomic drivers and downstream effectors of Wnt signaling in prostate cancer and the therapeutic potential of targeting this pathway in prostate cancer have not been fully established. Here we analyzed Wnt/β-catenin signaling in prostate cancer and identified effectors distinct from those found in other tissues, including aryl hydrocarbon receptor and RUNX1, which are linked to stem cell maintenance, and ROR1, a noncanonical Wnt5a coreceptor. Wnt/β-catenin signaling–mediated increases in ROR1 enhanced noncanonical responses to Wnt5a. Regarding upstream drivers, APC genomic loss, but not its epigenetic downregulation commonly observed in prostate cancer, was strongly associated with Wnt/β-catenin pathway activation in clinical samples. Tumor cell upregulation of the Wnt transporter Wntless (WLS) was strongly associated with Wnt/β-catenin pathway activity in primary prostate cancer but also associated with both canonical and noncanonical Wnt signaling in mCRPC. IHC confirmed tumor cell WLS expression in primary prostate cancer and mCRPC, and patient-derived prostate cancer xenografts expressing WLS were responsive to treatment with Wnt synthesis inhibitor ETC-1922159. These findings reveal that Wnt/β-catenin signaling in prostate cancer drives stem cell maintenance and invasion and primes for noncanonical Wnt signaling through ROR1. They further show that autocrine Wnt production is a nongenomic driver of canonical and noncanonical Wnt signaling in prostate cancer, which can be targeted with Wnt synthesis inhibitors to suppress tumor growth. Significance: This work provides fundamental insights into Wnt signaling and prostate cancer cell biology and indicates that a subset of prostate cancer driven by autocrine Wnt signaling is sensitive to Wnt synthesis inhibitors.
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Wu, Christina C. N., Michael Y. Choi, Fitzgerald Lao, Thomas J. Kipps, and Dennis A. Carson. "Inhibition Of Wnt Signaling In Chronic Lymphocytic Leukemia Has Synergistic Cytotoxicity With Ibrutinib." Blood 122, no. 21 (November 15, 2013): 5306. http://dx.doi.org/10.1182/blood.v122.21.5306.5306.
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Abstract The Wnt pathway plays a major role in early embryonic development and in various cancers. We found that CLL cells have activated Wnt-signaling (Proc Natl Acad SciUSA 2004, PMID: 14973184) and express genes commonly associated with B-cell progenitors or stem cells, especially the Wnt factor-related genes such as LEF1, Wnt16, and Frizzled3 (FZD3). Also, compared to normal B lymphocytes, CLL cells express high levels of the putative cancer stem cell marker Aldehyde Dehydrogenase (ALDH), especially those CLL cells with high-risk prognostic features (Leuk and Lymph, 2013, PMID 22784365) and are highly sensitive to inhibitors of Wnt signaling (Proc Natl Acad SciUSA 2004, PMID: 3156152). Finally, next generation DNA sequencing studies have identified mutations in 12 different Wnt pathway genes in 15-20% of CLL patients. Collectively, the results of these studies imply that Wnt-signaling may be an excellent target for developing effective novel therapies for patients with CLL (Oncotarget 2011, PMID: 21860066). We compared different classes of Wnt inhibitors identified by screening of natural compound and small molecule libraries for cytotoxicity in primary leukemic cells from patients with CLL. Among all the Wnt inhibitors tested, Salinomycin and Agelastatin (naturally occurring compounds targeting LRP5/6 degradation or LEF1 down-regulation as previously reported by our groups) consistently showed dose dependent cytotoxicity at concentrations lower than 1 µM. In contrast, small molecule Wnt inhibitors targeting more proximal elements of the Wnt pathway, porcupine (Wnt-C59) and tankyrase, (XAV-939) had little direct effect on in vitro CLL cell viability even at 10 µM. The Wnt inhibitors were also utilized as tool compounds to evaluate the effect of combined inhibition of the Wnt pathway and other pathways. Interestingly, we identified synergistic activity between Wnt inhibitors and other inhibitors, including Ibrutinib and Idelalisib. By colorimetric and flow cytometry assays, we demonstrated that significant cell death was induced with combinations of the agents at concentrations at which little or no cytotoxicity was seen with either agent alone. The studies further demonstrate that the Wnt pathway is a viable target for the treatment of CLL and may potentiate other emerging CLL therapies. Disclosures: Kipps: Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Janssen Pharmaceuticals: Speakers Bureau; Abbvie: Membership on an entity’s Board of Directors or advisory committees, Research Funding.
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Cruciat, C. M., and C. Niehrs. "Secreted and Transmembrane Wnt Inhibitors and Activators." Cold Spring Harbor Perspectives in Biology 5, no. 3 (October 19, 2012): a015081. http://dx.doi.org/10.1101/cshperspect.a015081.
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Wang, Siqing, Lei Shi, Hongwei Xu, Chunjiao Xu, Maurizio Zangari, Guido J. Tricot, and Fenghuang Zhan. "Combination of ATRA with a COX2 Inhibitor Induces Synergistic Effects On RARalpha2-Expressing Multiple Myeloma (MM) Cells." Blood 114, no. 22 (November 20, 2009): 2809. http://dx.doi.org/10.1182/blood.v114.22.2809.2809.
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Abstract Abstract 2809 Poster Board II-785 We recently observed that ATRA treatment selectively kills RARalpha2-expressing, while sparing RARalpha2-deficient MM cells. Previous investigations in the colon cancer cells have shown that ATRA inhibits WNT signaling through down-regulation of COX-2. Therefore, we wanted to evaluate the role of WNT signaling in ATRA-induced cell death and growth inhibition of RARalpha2-expressing myeloma cells. To our surprise, we found that ATRA treatment activated but not inhibited WNT signaling in RARalpha2-expressing myeloma cells, based on increased β-catenin levels in ATRA-treated cells. ATRA exerted minimal effects on activation of WNT signaling pathway in RARalpha2-deficient MM cells, and forced expression of RARalpha2 in RARalpha2-deficient cells restored the stimulatory activities of ATRA on the WNT signaling pathway, demonstrating that RARalpha2 expression is required for the ATRA-induced stimulation of WNT signaling in MM cells. Lithium chloride (LiCl) treatment, which activates WNT signaling, partially abrogated ATRA-induced cell death and growth inhibition in RARalpha2-expressing cells, indicating that ATRA-induced activation of WNT signaling resulted in ATRA-resistance and decreased killing of MM cells, suggesting that a combination of targeting WNT signaling pathway and ATRA treatment is necessary for ATRA-based therapy of RARalpha2-expressing myeloma. COX-2 inhibition blocks WNT signaling in colon cancer. Similarly, we found that a COX-2 inhibitor CAY10404 also blocked WNT signaling in RARalpha2-expressing cells as well as in ATRA-treated cells. Interestingly, CAY10404 activated MEK/ERK signaling pathway, while ATRA abrogated CAY10404-induced activation of MEK/ERK signaling pathway. These results demonstrate that the combination of ATRA and COX-2 inhibitor exerts synergistic inhibitory effects on both WNT and MEK/ERK signaling pathways. A combination of ATRA and the COX-2 inhibitor resulted in synergistic cytotoxicity of RARalpha2-expressing MM cells in-vitro. More importantly, the combination of ATRA and CAY10404 also resulted in a synergistic growth inhibition of established MM tumors in SCID mice. Our study demonstrates the importance of targeting WNT signaling in ATRA-based therapy in RARalpha2-expressing myeloma and provides a rationale for the combinational use of ATRA and COX-2 inhibitors. Disclosures: No relevant conflicts of interest to declare.
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Zhang, Na, Junquan Lin, Jiah Shin Chin, Christian Wiraja, Chenjie Xu, Duncan Angus McGrouther, and Sing Yian Chew. "Delivery of Wnt inhibitor WIF1 via engineered polymeric microspheres promotes nerve regeneration after sciatic nerve crush." Journal of Tissue Engineering 13 (January 2022): 204173142210874. http://dx.doi.org/10.1177/20417314221087417.
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Injuries within the peripheral nervous system (PNS) lead to sensory and motor deficits, as well as neuropathic pain, which strongly impair the life quality of patients. Although most current PNS injury treatment approaches focus on using growth factors/small molecules to stimulate the regrowth of the injured nerves, these methods neglect another important factor that strongly hinders axon regeneration—the presence of axonal inhibitory molecules. Therefore, this work sought to explore the potential of pathway inhibition in promoting sciatic nerve regeneration. Additionally, the therapeutic window for using pathway inhibitors was uncovered so as to achieve the desired regeneration outcomes. Specifically, we explored the role of Wnt signaling inhibition on PNS regeneration by delivering Wnt inhibitors, sFRP2 and WIF1, after sciatic nerve transection and sciatic nerve crush injuries. Our results demonstrate that WIF1 promoted nerve regeneration ( p < 0.05) after sciatic nerve crush injury. More importantly, we revealed the therapeutic window for the treatment of Wnt inhibitors, which is 1 week post sciatic nerve crush when the non-canonical receptor tyrosine kinase (Ryk) is significantly upregulated.
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Gunn, W. Grady, Ulf Krause, Narae Lee, and Carl A. Gregory. "Pharmaceutical inhibition of glycogen synthetase kinase-3β reduces multiple myeloma–induced bone disease in a novel murine plasmacytoma xenograft model." Blood 117, no. 5 (February 3, 2011): 1641–51. http://dx.doi.org/10.1182/blood-2010-09-308171.
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Abstract Multiple myeloma (MM) is a malignancy of plasma cells that accumulate in the bone marrow. MM is incurable with approximately 100 000 patients currently in the United States and 20 000 new cases diagnosed yearly. The malignancy causes displacement of hematopoiesis and formation of osteolytic bone lesions also known as myeloma bone disease (MBD). At diagnosis, 79% of patients suffer from MBD associated with severe pain and increased mortality. Wnt inhibitors secreted by MM cells inhibit osteogenesis and promote osteoclastogenesis, therefore rapid targeting of Wnt inhibitors is necessary to prevent potentially irreversible effects on the stroma, which could lead to incurable MBD. Inhibition of glycogen synthetase kinase-3β (GSK3β) causes accelerated Wnt signaling and enhanced osteogenesis in mesenchymal stem/progenitor cells, irrespective of the extracellular concentration of Wnt inhibitors. Our primary goal of this study was to evaluate a GSK3β inhibitor (6-bromoindirubin-3′-oxime BIO) for amelioration of bone destruction in a murine model of MBD. When measured using histomorphometry, peritumoral BIO administration improved bone quality at the bone-tumor interface and, surprisingly, increased histologically apparent tumor necrosis. Furthermore, in vitro assays demonstrated a proapoptotic effect on numerous MM cell lines. These preliminary data suggest that pharmaceutical GSK3β inhibition may improve bone quality in myeloma and other malignant bone diseases.
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Weich, Alexander, Dorothee Rogoll, Sophia Gawlas, Lars Mayer, Wolfgang Weich, Judit Pongracz, Theodor Kudlich, Alexander Meining, and Michael Scheurlen. "Wnt/β-Catenin Signaling Regulates CXCR4 Expression and [68Ga] Pentixafor Internalization in Neuroendocrine Tumor Cells." Diagnostics 11, no. 2 (February 22, 2021): 367. http://dx.doi.org/10.3390/diagnostics11020367.
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Loss of Somatostatin Receptor 2 (SSTR2) expression and rising CXC Chemokine Receptor Type 4 (CXCR4) expression are associated with dedifferentiation in neuroendocrine tumors (NET). In NET, CXCR4 expression is associated with enhanced metastatic and invasive potential and worse prognosis but might be a theragnostic target. Likewise, activation of Wnt/β-catenin signaling may promote a more aggressive phenotype in NET. We hypothesized an interaction of the Wnt/β-catenin pathway with CXCR4 expression and function in NET. The NET cell lines BON-1, QGP-1, and MS-18 were exposed to Wnt inhibitors (5-aza-CdR, quercetin, and niclosamide) or the Wnt activator LiCl. The expressions of Wnt pathway genes and of CXCR4 were studied by qRT-PCR, Western blot, and immunohistochemistry. The effects of Wnt modulators on uptake of the CXCR4 ligand [68Ga] Pentixafor were measured. The Wnt activator LiCl induced upregulation of CXCR4 and Wnt target gene expression. Treatment with the Wnt inhibitors had opposite effects. LiCl significantly increased [68Ga] Pentixafor uptake, while treatment with Wnt inhibitors decreased radiopeptide uptake. Wnt pathway modulation influences CXCR4 expression and function in NET cell lines. Wnt modulation might be a tool to enhance the efficacy of CXCR4-directed therapies in NET or to inhibit CXCR4-dependent proliferative signaling. The underlying mechanisms for the interaction of the Wnt pathway with CXCR4 expression and function have yet to be clarified.
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Fuentes, Rolly Garnace, Gio Martin A. Ocfemia, and Galileo Gregory Abrasaldo. "Antibacterial and Zebrafish-based Screening for Wnt Signal Inhibitory Activities of Syzygium polycephaloides (C.B. Robb. Merr.) Bark Extracts." ASM Science Journal 15 (May 17, 2021): 1–6. http://dx.doi.org/10.32802/asmscj.2021.438.
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Syzygium polycephaloides, a plant native to Southeast Asia, is used to cure common illnesses. In this study, the methanolic bark extracts of S. polycephaloides was evaluated for their antibacterial activity and screened for their Wnt signal inhibitory activity using zebrafish-based assay. In the antibacterial assay, the extracts were tested against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeroginosa, and Escherichia coli using disk diffusion assay. On the other hand, zebrafish-based screening was used to determine the inhibitory potential of S. polycephaloides against the Wnt signal. Zebrafish embryos were treated with LiCl to upregulate the Wnt signal which produces eyeless phenotype. The methanolic extracts had antibacterial activity against the test microorganisms except P. aeruginosa. After fractionation, ethyl acetate (EtOAc) and aqueous fractions exhibited wide-spectrum antibacterial activity. For the Wnt signal inhibitory activity screening, the LiCl-treated embryos were rescued to their normal eye development after treatment with the S. polycephaloides bark extracts (100 g/mL). The results suggest that the extracts may have inhibited the Wnt signal. This study shows that the S. polycephaloides is a potent source of antibacterial compounds and Wnt inhibitors.
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Kavalerchik, Edward, Jason Gotlib, Ifat Geron, Annelie Abrahamsson, Wolfgang Wrasidlo, Daniel Goff, Desheng Lu, et al. "Inhibition of Chronic Myelogenous Leukemia Stem Cells with Novel Wnt Antagonists." Blood 108, no. 11 (November 16, 2006): 238. http://dx.doi.org/10.1182/blood.v108.11.238.238.
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Abstract Introduction A growing proportion of chronic myelogenous leukemia (CML) patients show evidence of disease progression. Recent research suggests that leukemia stem cells (LSC) that share phenotypic characteristics with granulocyte-macrophage progenitors (GMP) are involved in CML progression. These LSC have aberrantly gained self-renewal capacity as a result of enhanced Wnt/beta-catenin signaling. We assayed the capacity of novel Wnt/beta-catenin antagonists to inhibit CML LSC. Methods To assay the efficacy of a novel Wnt inhibitor, MC-001, HEK293 cells were transfected with a Wnt-dependent reporter gene and expression plasmid for Dsh. After 16h, the cells were treated for 24 h with MCC-001, a novel marine sponge derived inhibitor, at varying concentrations and the reporter gene activity was measured. All cells were also transfected with a b-gal reporter gene to control for transfection efficiency. To assess the effects of MCC-001 and other Wnt inhibitors on Wnt/beta-catenin induced self-renewal, hematopoietic stem cells (HSC), GMP and lineage positive cells from normal (n=8) and advanced phase CML (n=8) peripheral blood and marrow (n=8) were clone sorted with the aid of a FACS Aria into methocult media (Stem Cell Technologies) with or without Wnt inhibitors including recombinant Dkk1, lentiviral axin or MCC-001. On day 10, individual colonies were plucked and replated in new methylcellulose and the replating efficiency determined at day 10. To establish an in vivo CML LSC model, HSC, GMP and lineage positive cells were transduced with a lentiviral luciferase GFP for 48 hours and transplanted intrahepatically into newborn immunocompromised mice (RAG2−/−gamma−/−) mice that facilitate high levels of human hematopoietic progenitor engraftment. Results The HEK293 beta-catenin reporter assay revealed that the MC-001 IC50 was 2.1 microM. In comparative Wnt inhibitor replating assays (n=8), recombinant Dkk1 did not inhibit CML HSC (n=8) while lentiviral axin and MCC-001 (at 2 and 10 microM) inhibited both CML HSC and CML GMP at doses that spared normal HSC replating (Figure 1). Transplantation of CML HSC, GMP and lineage positive cells into RAG2−/−gamma−/− mice demonstrated that only CML GMP provided serial transplantation potential and thus, were enriched for the LSC population (Figure 2). Conclusions Selective Wnt/beta-catenin inhibition with a marine sponge derived beta-catenin antagonist, MCC-001, blocks in vitro replating capacity of CML LSC at doses that spare normal HSC. Current experiments focus on in vivo inhibition of LSC self-renewal with novel Wnt inhibitors in a robust CML LSC bioluminescent imaging model (Figure 2). Figure 1. Chronic Myelogenous Leukemia Stem Cell Inhibition with MCC-001: A novel β-catenin Inhibitor Figure 1. Chronic Myelogenous Leukemia Stem Cell Inhibition with MCC-001: A novel β-catenin Inhibitor Figure 2. Bioluminescent Chronic Myelogenous Leukemia Stem Cell Transplantation Model. Figure 2. Bioluminescent Chronic Myelogenous Leukemia Stem Cell Transplantation Model.
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Kim, Anthony S., Daniel H. Lowenstein, and Samuel J. Pleasure. "Wnt receptors and Wnt inhibitors are expressed in gradients in the developing telencephalon." Mechanisms of Development 103, no. 1-2 (May 2001): 167–72. http://dx.doi.org/10.1016/s0925-4773(01)00342-2.
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Jackson, Sadhana, Amelie Vezina, Nabanita Kundu, and Robert Robey. "BIOL-01. THE RELATIONSHIP OF BRAIN ENDOTHELIAL WNT SIGNAL INHIBITION ON BLOOD-TUMOR BARRIER INTEGRITY." Neuro-Oncology 23, Supplement_1 (June 1, 2021): i3. http://dx.doi.org/10.1093/neuonc/noab090.009.
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Abstract The blood-tumor barrier (BTB) is the primary site of nutrient and drug transport to tumor cells such as malignant gliomas. Yet, signaling pathways and factors influencing BTB permeability are poorly understood. Previous studies demonstrate the role of WNT/β-catenin signaling in establishing and fortifying blood-brain barrier integrity in a non-diseased state. Additionally, WNT proteins are highly expressed in gliomas and their surrounding vasculature. Thus, we propose inhibition of WNT/β-catenin signaling at the brain endothelium of malignant glioma can impair BTB integrity to enhance permeability for select cytotoxic agents. We used immortalized mouse brain endothelial cells (bEnd.3), akin to brain tumor endothelium, treated for 24 hours with WNT inhibitors (ICG-001, IWR-1, and LGK974). Inhibition of WNT/β-catenin signaling was confirmed by gene expression of transcription factors (Tcf4 and Birc5). Cell viability was confirmed by CellTiter Glo®. Brain endothelial cell-cell interaction was evaluated by cell impedance and resistance via the Agilent xCELLigence and ABP TEER24 systems. Using qPCR and flow cytometry, we observed changes in expression and function of Abcb1 and Abcg2 transporters. Using an in vitro BTB (bEnd.3 cells and mouse H3.3WT/K27 glioma cells) we evaluated the effect of WNT inhibition on permeability and glioma viability. We found that all the inhibitors downregulated Tcf4 and Birc5 in brain endothelium dose-dependently. Viability with inhibitors demonstrated an IC50 of 28μM for ICG-001, and 42μM for both IWR-1 and LGK974. Endothelial cell-cell interaction was transiently decreased by approximately 50% with all inhibitors at 30 minutes; increasing closer to baseline after 2-4hrs. All WNT inhibitors dose-dependently decreased Abcg2 transporter expression and function. While In vitro BTB studies are ongoing, preliminary findings demonstrate increasing permeability of BTB amongst H3.3K27 glioma cells. Our results demonstrate potential of WNT inhibitors to modulate BTB integrity and drug efflux function. More studies are warranted to explore WNT/β-catenin signaling inhibition on BTB in vivo.
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Nemade, Harshal, Aviseka Acharya, Umesh Chaudhari, Erastus Nembo, Filomain Nguemo, Nicole Riet, Hinrich Abken, Jürgen Hescheler, Symeon Papadopoulos, and Agapios Sachinidis. "Cyclooxygenases Inhibitors Efficiently Induce Cardiomyogenesis in Human Pluripotent Stem Cells." Cells 9, no. 3 (February 27, 2020): 554. http://dx.doi.org/10.3390/cells9030554.
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Application of human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is limited by the challenges in their efficient differentiation. Recently, the Wingless (Wnt) signaling pathway has emerged as the key regulator of cardiomyogenesis. In this study, we evaluated the effects of cyclooxygenase inhibitors on cardiac differentiation of hPSCs. Cardiac differentiation was performed by adherent monolayer based method using 4 hPSC lines (HES3, H9, IMR90, and ES4SKIN). The efficiency of cardiac differentiation was evaluated by flow cytometry and RT-qPCR. Generated hPSC-CMs were characterised using immunocytochemistry, electrophysiology, electron microscopy, and calcium transient measurements. Our data show that the COX inhibitors Sulindac and Diclofenac in combination with CHIR99021 (GSK-3 inhibitor) efficiently induce cardiac differentiation of hPSCs. In addition, inhibition of COX using siRNAs targeted towards COX-1 and/or COX-2 showed that inhibition of COX-2 alone or COX-1 and COX-2 in combination induce cardiomyogenesis in hPSCs within 12 days. Using IMR90-Wnt reporter line, we showed that inhibition of COX-2 led to downregulation of Wnt signalling activity in hPSCs. In conclusion, this study demonstrates that COX inhibition efficiently induced cardiogenesis via modulation of COX and Wnt pathway and the generated cardiomyocytes express cardiac-specific structural markers as well as exhibit typical calcium transients and action potentials. These cardiomyocytes also responded to cardiotoxicants and can be relevant as an in vitro cardiotoxicity screening model.
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Sonderegger, S., P. Haslinger, A. Sabri, J. V. Otten, C. Leisser, C. Fiala, and M. Knofler. "145. WINGLESS (WNT) 3A INDUCES TROPHOBLAST MIGRATION AND MATRIX METALLOPROTEINASE-2 SECRETION THROUGH CANONICAL WNT SIGNALLING AND PROTEIN KINASE B/AKT ACTIVATION." Reproduction, Fertility and Development 22, no. 9 (2010): 63. http://dx.doi.org/10.1071/srb10abs145.
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Human placenta and trophoblasts express WNT ligands and WNT receptors suggesting a role for WNT-signalling in placental development. Indeed, a recombinant WNT ligand was recently shown to promote trophoblast migration/invasion, however, the involved signalling cascades and their target genes have not been elucidated. The aim was to investigate signal transduction via canonical WNT-signalling or phosphatidylinositide 3-kinase (PI3K)/AKT-signalling, their cross-talk as well as trophoblast-specific protease expression in trophoblastic SGHPL-5 cells and primary 1st trimester extravillous trophoblasts (EVT). WNT3A-dependent activation/phosphorylation of AKT (pAKT) and the down-stream kinaseglycogen synthase kinase (GSK)-3β were determined by Western blotting (WB). WNT3A-induced canonical WNT-signalling was analysed by luciferase reporter assay (TOPFlash) and nuclear recruitment of β-catenin. Trophoblast migration was studied using transwell assays and villous explant cultures. MMP2 expression/activation was investigated by qRT-PCR and WB/gelatine-zymography of supernatants. All experiments were performed +/– inhibitors of AKT-signalling or canonical WNT-signalling using LY294002 (PI3K inhibitor) or recombinant Dickkopf-1 (DKK1). WNT3A induced pAKT, luciferase expression of the canonical WNT reporter (P < 0.05) as well as accumulation of nuclear β-catenin. Inhibition of PI3K abolished WNT-dependent pAKT, pGSK-3β and cell migration, but did not affect TOPFlash activity or appearance of nuclear β-catenin. Inhibition through DKK1 did not influence pAKT and pGSK-3β, but decreased WNT reporter activity, nuclear β-catenin and cell migration. Both inhibitors decreased WNT3A-induced MMP2 expression in SGHPL-5 cells and pure EVTs (P < 0.05). WNT3A activates PI3K/AKT as well as canonical WNT-signalling through distinct receptors in invasive trophoblasts, since DKK1 did not activate the particular kinase. Although cross-talk between PI3K/AKT and canonical WNT-signalling has been observed in some cell types, these pathways seem to act independently in trophoblasts. However, both pathways promote Wnt-dependent migration and expression of MMP2. This is the 1st study identifying MMP2 as a novel target gene of canonical WNT-signalling in trophoblast.
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Tan, Mengtian, Lai Jiang, Yinglei Li, and Wei Jiang. "Dual Inhibition of BMP and WNT Signals Promotes Pancreatic Differentiation from Human Pluripotent Stem Cells." Stem Cells International 2019 (December 1, 2019): 1–15. http://dx.doi.org/10.1155/2019/5026793.
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Pathological or functional loss of pancreatic beta cells is the cause of diabetes. Understanding how signaling pathways regulate pancreatic lineage and searching for combinations of signal modulators to promote pancreatic differentiation will definitely facilitate the robust generation of functional beta cells for curing hyperglycemia. In this study, we first tested the effect of several potent BMP inhibitors on pancreatic differentiation using human embryonic stem cells. Next, we examined the endodermal lineage bias upon potent BMP inhibitor treatment and further checked the crosstalk between signal pathways governing endodermal lineage determination. Furthermore, we improved current pancreatic differentiation system based on the signaling pathway study. Finally, we used human-induced pluripotent stem cells to validate our finding. We found BMP inhibitors indeed not only blocked hepatic lineage but also impeded intestinal lineage from human definitive endoderm unexpectedly. Signaling pathway analysis indicated potent BMP inhibitor resulted in the decrease of WNT signal activity and inhibition of WNT could contribute to the improved pancreatic differentiation. Herein, we combined the dual inhibition of BMP and WNT signaling and greatly enhanced human pancreatic progenitor differentiation as well as beta cell generation from both embryonic stem cells and induced pluripotent stem cells. Conclusively, our present work identified the crosstalk between the BMP and WNT signal pathways during human endoderm patterning and pancreas specification, and provided an improved in vitro pancreatic directed differentiation protocol from human pluripotent stem cells.
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Janovská, Pavlína, Emmanuel Normant, Hari Miskin, and Vítězslav Bryja. "Targeting Casein Kinase 1 (CK1) in Hematological Cancers." International Journal of Molecular Sciences 21, no. 23 (November 27, 2020): 9026. http://dx.doi.org/10.3390/ijms21239026.
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The casein kinase 1 enzymes (CK1) form a family of serine/threonine kinases with seven CK1 isoforms identified in humans. The most important substrates of CK1 kinases are proteins that act in the regulatory nodes essential for tumorigenesis of hematological malignancies. Among those, the most important are the functions of CK1s in the regulation of Wnt pathways, cell proliferation, apoptosis and autophagy. In this review we summarize the recent developments in the understanding of biology and therapeutic potential of the inhibition of CK1 isoforms in the pathogenesis of chronic lymphocytic leukemia (CLL), other non-Hodgkin lymphomas (NHL), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and multiple myeloma (MM). CK1δ/ε inhibitors block CLL development in preclinical models via inhibition of WNT-5A/ROR1-driven non-canonical Wnt pathway. While no selective CK1 inhibitors have reached clinical stage to date, one dual PI3Kδ and CK1ε inhibitor, umbralisib, is currently in clinical trials for CLL and NHL patients. In MDS, AML and MM, inhibition of CK1α, acting via activation of p53 pathway, showed promising preclinical activities and the first CK1α inhibitor has now entered the clinical trials.
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Kleszcz, Robert, and Jarosław Paluszczak. "The Wnt Signaling Pathway Inhibitors Improve the Therapeutic Activity of Glycolysis Modulators against Tongue Cancer Cells." International Journal of Molecular Sciences 23, no. 3 (January 23, 2022): 1248. http://dx.doi.org/10.3390/ijms23031248.
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Excessive glucose metabolism and disruptions in Wnt signaling are important molecular changes present in oral cancer cells. The aim of this study was to evaluate the effects of the combinatorial use of glycolysis and Wnt signaling inhibitors on viability, cytotoxicity, apoptosis induction, cell cycle distribution and the glycolytic activity of tongue carcinoma cells. CAL 27, SCC-25 and BICR 22 tongue cancer cell lines were used. Cells were treated with inhibitors of glycolysis (2-deoxyglucose and lonidamine) and of Wnt signaling (PRI-724 and IWP-O1). The effects of the compounds on cell viability and cytotoxicity were evaluated with MTS and CellTox Green tests, respectively. Apoptosis was evaluated by MitoPotential Dye staining and cell cycle distribution by staining with propidium iodide, followed by flow cytometric cell analysis. Glucose and lactate concentrations in a culture medium were evaluated luminometrically. Combinations of 2-deoxyglucose and lonidamine with Wnt pathway inhibitors were similarly effective in the impairment of oral cancer cells’ survival. However, the inhibition of the canonical Wnt pathway by PRI-724 was more beneficial, based on the glycolytic activity of the cells. The results point to the therapeutic potential of the combination of low concentrations of glycolytic modulators with Wnt pathway inhibitors in oral cancer cells.
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Andrey Voronkov and Stefan Krauss. "Wnt/beta-Catenin Signaling and Small Molecule Inhibitors." Current Pharmaceutical Design 19, no. 4 (December 10, 2012): 634–64. http://dx.doi.org/10.2174/1381612811306040634.
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Voronkov, Andrey, and Stefan Krauss. "Wnt/beta-Catenin Signaling and Small Molecule Inhibitors." Current Pharmaceutical Design 19, no. 4 (February 1, 2013): 634–64. http://dx.doi.org/10.2174/138161213804581837.
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Ray, Katrina. "Therapeutic strategies for cholangiocarcinoma—wishing on WNT inhibitors?" Nature Reviews Gastroenterology & Hepatology 12, no. 4 (March 10, 2015): 187. http://dx.doi.org/10.1038/nrgastro.2015.39.
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Xu, Congdi, Xinyu Hu, Yantao Fan, Ling Zhang, Zhengliang Gao, and Chunhui Cai. "Wif1 Mediates Coordination of Bone Morphogenetic Protein and Wnt Signaling in Neural and Glioma Stem Cells." Cell Transplantation 31 (January 2022): 096368972211345. http://dx.doi.org/10.1177/09636897221134540.
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Wnts, bone morphogenetic protein (BMP), and fibroblast growth factor (FGF) are paracrine signaling pathways implicated in the niche control of stem cell fate decisions. BMP-on and Wnt-off are the dominant quiescent niche signaling pathways in many cell types, including neural stem cells (NSCs). However, among the multiple inhibitory family members of the Wnt pathway, those with direct action after BMP4 stimulation in NSCs remain unclear. We examined 11 Wnt inhibitors in NSCs after BMP4 treatment. Wnt inhibitory factor 1 (Wif1) has been identified as the main factor reacting to BMP4 stimuli. RNA sequencing confirmed that Wif1 was markedly upregulated after BMP4 treatment in different gene expression analyses. Similar to the functional role of BMP4, Wif1 significantly decreased the cell cycle of NSCs and significantly inhibited cell proliferation ( P < 0.05). Combined treatment with BMP4 and Wif1 significantly enhanced the inhibition of cell growth compared with the single treatment ( P < 0.05). Wif1 expression was clearly lower in glioblastoma and low-grade glioma samples than in normal samples ( P < 0.05). A functional analysis revealed that both BMP4 and Wif1 could decrease glioma cell growth. These effects were abrogated by the BMP inhibitor Noggin. The collective findings demonstrate that Wif1 plays a key role in quiescent NSC homeostasis and glioma cell growth downstream of BMP-on signaling. The functional roles of Wif1/BMP4 in glioma cells may provide a technical basis for regenerative medicine, drug discovery, and personal molecular therapy in future clinical treatments.
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Koo, Bon-Kyoung, Johan H. van Es, Maaike van den Born, and Hans Clevers. "Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3-mutant neoplasia." Proceedings of the National Academy of Sciences 112, no. 24 (May 28, 2015): 7548–50. http://dx.doi.org/10.1073/pnas.1508113112.
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Rnf43 (RING finger protein 43) and Znrf3 (zinc/RING finger protein 3) (RZ) are two closely related transmembrane E3 ligases, encoded by Wnt target genes, that remove surface Wnt (wingless-int) receptors. The two genes are mutated in various human cancers. Such tumors are predicted to be hypersensitive to, yet still depend on, secreted Wnts. We previously showed that mutation of RZ in the intestine yields rapidly growing adenomas containing LGR5+ (leucine-rich repeat-containing G-protein coupled receptor 5) stem cells and Wnt3-producing Paneth cells. We now show that removal of Paneth cells by Math1 mutation inhibits RZ−/− tumor formation. Similarly, deletion of Wnt3 inhibits tumorigenesis. Treatment of mice carrying RZ−/− intestinal neoplasia with a small molecule Wnt secretion inhibitor (porcupine inhibitor C59) strongly inhibited growth, whereas adjacent normal crypts remained intact. These results establish that paracrine Wnt secretion is an essential driver of RZ−/− tumor growth and imply that a therapeutic window exists for the use of porcupine inhibitors for RZ-mutant cancers.
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Shen, Chen, Anmada Nayak, Ricardo A. Melendez, Daniel T. Wynn, Joshua Jackson, Ethan Lee, Yashi Ahmed, and David J. Robbins. "Casein Kinase 1α as a Regulator of Wnt-Driven Cancer." International Journal of Molecular Sciences 21, no. 16 (August 18, 2020): 5940. http://dx.doi.org/10.3390/ijms21165940.
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Wnt signaling regulates numerous cellular processes during embryonic development and adult tissue homeostasis. Underscoring this physiological importance, deregulation of the Wnt signaling pathway is associated with many disease states, including cancer. Here, we review pivotal regulatory events in the Wnt signaling pathway that drive cancer growth. We then discuss the roles of the established negative Wnt regulator, casein kinase 1α (CK1α), in Wnt signaling. Although the study of CK1α has been ongoing for several decades, the bulk of such research has focused on how it phosphorylates and regulates its various substrates. We focus here on what is known about the mechanisms controlling CK1α, including its putative regulatory proteins and alternative splicing variants. Finally, we describe the discovery and validation of a family of pharmacological CK1α activators capable of inhibiting Wnt pathway activity. One of the important advantages of CK1α activators, relative to other classes of Wnt inhibitors, is their reduced on-target toxicity, overcoming one of the major impediments to developing a clinically relevant Wnt inhibitor. Therefore, we also discuss mechanisms that regulate CK1α steady-state homeostasis, which may contribute to the deregulation of Wnt pathway activity in cancer and underlie the enhanced therapeutic index of CK1α activators.
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Bravo, Dalibel, Kristen L. Shogren, Scott M. Riester, Eric R. Wagner, James L. Herrick, Scott H. Okuno, Michael J. Yaszemski, and Avudaiappan Maran. "Wnt antagonists in osteosarcoma patients." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 10531. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.10531.
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10531 Background: Osteosarcoma (OS) is a clinically challenging primary malignant bone tumor that has a high rateof local recurrence and metastasis. Disease free survival has been reported to be as low as 19% despite contemporary chemotherapy regimens and surgery. Wnt signaling is known to play a role in osteogenesis and cancer pathogenesis, therefore is a promising target for therapeutic intervention in OS. Secreted Frizzled Related Proteins (sFRPs), Dickkopf-1 (DKK1), and Sclerostin (SOST) are secreted Wnt inhibitor proteins that regulate Wnt signaling in bone. This study investigates the activity of sFRP3, DKK1, and SOST in serum from OS patients with the goal of developing therapeutic Wnt inhibitors and clinically useful biomarkers. Methods: Enzyme linked immunosorbent assayswere used to quantify sFRP3, DKK1 and SOST levels in human serum (n=40 pairs; 20 OS patients, 20 aged matched non-diseased controls). Patients were stratified into 2 age groups: >35 (n=26 pairs) and <30 (n=14 pairs) years of age. Clinical data from the medical records was correlated with experimental results. Using a Wilcoxon signed rank test, a p–value <0.05 was significant. Results: sFRP3 levels were significantly decreased in 55% (22/40) of diseased samples compared to 20% (8/40) of the non-diseased controls (p= 0.007). DKK1 levels were elevated in 40% (16/40) of OS samples compared to 30% (12/40) of the non-diseased controls (p= 0.08). SOST levels were increased in 42.5% (17/40) of diseased samples compared to 32.5% (13/40) of the non-diseased controls (p= 0.38). When stratified by age, the younger patients showed a statistically significant decrease in sFRP3 expression (p<0.001). Serum levels of sFRP3, DKK1, and SOST were not statistically significant between metastatic and non-metastatic OS. Conclusions: Serum sFRP3 levels were significantly decreased in OS patients, a difference that was even more pronounced in the pediatric strata. Since sFRP3 is differentially expressed in patient serum it has potential as a clinical biomarker for initial tumor diagnosis and early detection of recurrence. Decreased sFRP3 expression may be responsible for the up regulation of Wnt signaling in OS. Wnt inhibitors such as sFRP3 have potential as therapeutic agents in OS warranting further investigation.
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Fu, Wen-bin, Wei Eric Wang, and Chun-yu Zeng. "Wnt signaling pathways in myocardial infarction and the therapeutic effects of Wnt pathway inhibitors." Acta Pharmacologica Sinica 40, no. 1 (July 12, 2018): 9–12. http://dx.doi.org/10.1038/s41401-018-0060-4.
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Zhang, Hao, Ya Bao, Chenglong Liu, Jianqi Li, Di Zhu, and Qingwei Zhang. "Recent advances in β-catenin/BCL9 protein–protein interaction inhibitors." Future Medicinal Chemistry 13, no. 10 (May 2021): 927–40. http://dx.doi.org/10.4155/fmc-2020-0357.
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Wnt/β-catenin signaling is crucial both in normal embryonic development and throughout the life of an organism. Moreover, aberrant Wnt signaling has been associated with various diseases, especially cancer and fibrosis. Recent research suggests that direct targeting of the β-catenin/BCL9 protein–protein interaction (PPI) is a promising strategy to block the Wnt pathway. Progress in understanding the cocrystalline complex and mechanism of action of the β-catenin/BCL9 interaction facilitates the discovery process of its inhibitors, but only a few inhibitors have been reported. In this review, the discovery and development of β-catenin/BCL9 PPI inhibitors in the areas of drug design, structure–activity relationships and biological and biochemical properties are summarized. In addition, perspectives for the future development of β-catenin/BCL9 PPI inhibitors are explored.
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Hao, Jing. "Abstract 5348: SEMA3C signaling confers resistance to Wnt Inhibition in glioblastoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5348. http://dx.doi.org/10.1158/1538-7445.am2022-5348.
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Abstract Background: Wnt signaling is widely dysregulated in cancer. The therapeutic potential of Wnt inhibitors appears promising in preclinical studies. However, they have uniformly failed clinical trials. How cancer cells develop Wnt inhibitor resistance is poorly understood. Current Wnt inhibitors are designed targeting either ligand or receptor. We hypothesized cancer cells will bypass ligand-receptor interaction through an unknown mechanism. We focused on the neurodevelopmental signaling program of Semaphorin 3C (Sema3C) that is upregulated in 85% of GBM and regulates glioma stem-cell-driven tumor progression. Methods: We analyzed the expression of Sema3C and TCF1 expression pattern in 32 human GBM samples by immunohistochemistry. GSC self-renewal was assessed by extreme limiting dilution, Edu incorporation, tumorsphere formation and cell survival assays in Sema3C silencing GSCs. Cell fractionation and immunofluorescence studies were performed to assess β-catenin sub-cellular localization in GSCs. GSC-derived mouse models were assessed for survival. Results: Porcupine inhibitor LGK974 reduced TCF1 expression in the GBM tumor mouse models, suggesting successful target engagement in vivo. However, it failed to prolong the overall survival. Sema3C expression strongly correlated with TCF1 expression in human GBM samples by immunohistochemical analysis. Genetic inhibition of Sema3C and TCF1 together prolonged animal survival more than either alone, indicating better control of Wnt pathway signaling with dual pathway blockade. Immunofluorescence and cell fractionation studies revealed that Sema3C signaling drove β-catenin nuclear accumulation. Sema3C regulates transactivation of Wnt target genes including TCF1, c-Myc and c-Met. Sema3C pathway activates Rac1. It is reported that Rac1 activates β-catenin and promotes β-catenin nuclear accumulation. In GSCs, constitutively active Rac1 restored β-catenin nuclear localization and rescued TCF1 and c-Myc down-regulation in the setting of Sema3C silencing. Sema3C can drive canonical Wnt signaling even when Wnt ligand secretion is blocked. Together, the data support that GSCs can escape Wnt inhibition through Sema3C and Rac1. Conclusions: Sema3C signaling drives canonical Wnt signaling, providing an escape mechanism for cancer cells despite Wnt ligand-receptor interruption. Sema3C-β-catenin signaling promotes GSC self-renewal and tumor progression. Upstream Wnt pathway inhibition alone is insufficient to control tumors. Our data provide a therapeutic strategy of dual blockade of Wnt and Sema3C pathways to provide clinically significant tumor control. Citation Format: Jing Hao. SEMA3C signaling confers resistance to Wnt Inhibition in glioblastoma [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 5348.
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Cai, Zhen, and Jie Hu. "Construction of Wif1-IgG1/Fc Recombinant Vector and Characterization of Its Expression in CHO Cells." Blood 108, no. 11 (November 16, 2006): 5207. http://dx.doi.org/10.1182/blood.v108.11.5207.5207.
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Abstract Wnt signalling dysregulation has been implicated in cancers, including lymphoma. The Initiation of Wnt signalling modulated by soluble Wnt ant agonists, including soluble frizzled related proteins, dickkopf proteins, and Wnt inhibitory factor-1 (Wif1). These natural inhibitors can be used directly as theraputic reagents for cancers. But the recombinant antagonist only give very low blood levels, are cleared rapidly from the body (only several hours) and must be administered daily via subcutaneous injection. Therefore, development of new forms of Wnts inhibitors with prolonged circulating half-life is of significant interest. Human IgG immunoglobulins have longer circulating half-life (21 days in humans). When fused with a Wnt inhibitor, its dimeric structure further increases the effective size and circulating half-life. Thus administration of vector plasmid may be every 2~3 week. Moreover, IgG Fc can interact with FcR of CTL, NK, MΦ, and complements and the target cells can be killed through ADCC and CDCC. We constructed a Wif1-IgG1/Fc expressing vector and expressed it in Chinese hamster ovum cells in order to seek effective methods to inhibit lymphoma growth. Wif1 and IgG/Fc cDNAs were amplified by RT-PCR from human lymphocyte and cloned into the eukaryotic expression vector pcDNA3.0 by direct cloning and the resultant recombinant plasmid pcDNA Wif1-IgG1/Fc was transfected into 293 cells with lipofectmin. The constitutively expressing cells were obtained by G418 screening. Expression of the fusion protein was confirmed by Western blot, the fusion protein was purified with affinity chromatography, and its’ biological activity was examined by flow cytometry, MTT colorimetry and ELISA. Our results show that the fusion protein significantly upregulated Wif1 density and promoted molt3 cell apoptosis, which was time dependent. The molt3 cell apoptosis induced by the fusion protein increased in the presence of NK cells or complements. Thus, we have successfully constructed and functionally expressed Wif1-IgG1/Fc fusion protein and shown that the purified fusion protein could kill molt3 cells through apoptosis and by ADCC and CDCC.
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A Harris, Jon, and Edward A Beutler. "Therapeutic window for Wnt-driven cancers: Role of Porcupine inhibitor." American Journal of BioMedicine 2, no. 2 (May 14, 2014): 78–86. http://dx.doi.org/10.18081/2333-5106/014-01/78-86.
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Wnt signaling plays a critical role in carcinogenesis; many studies over the last two decades have identified numerous signaling components that have helped to build a molecular framework for the many branches of the Wnt signal transduction pathway. However, the diverse function, integration and specificity of the Wnt signaling are still unclear. The success of Wnt pathway inhibitors has been limited for long-time by the narrow therapeutic window afforded by the requirement for Wnt signaling in normal tissue homeostasis and the lack of predictive biomarkers of response. Porcupine is a membrane bound O-acyltransferase enzyme that is required for and dedicated to palmitoylating Wnt ligands, a necessary step in the process of Wnt ligand secretion. Inhibition of Porcupine blocks Wnt dependent activities, including LRP6 phosphorylation and the expression of Wnt target genes, such as Axin2, which in turn reduces the growth of cancer cells dependent on autocrine or paracrine Wnt signaling. LGK974 is a highly potent, selective and orally bioavailable Porcupine inhibitor and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV–Wnt1, a human head and neck squamous cell carcinoma model (HN30) and RNF43-mutant pancreatic xenograft models. In this review, we will summarize the most recent advances in our understanding of these Wnt signaling pathways and the role of Porcupine in inhibition of Wnt activity.
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Funck-Brentano, Thomas, Karin H. Nilsson, Robert Brommage, Petra Henning, Ulf H. Lerner, Antti Koskela, Juha Tuukkanen, Martine Cohen-Solal, Sofia Movérare-Skrtic, and Claes Ohlsson. "Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice." Journal of Endocrinology 238, no. 1 (July 2018): 13–23. http://dx.doi.org/10.1530/joe-18-0153.
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WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.
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Bisson, Sarah-Kim, Roth-Visal Ung, and Fabrice Mac-Way. "Role of the Wnt/β-Catenin Pathway in Renal Osteodystrophy." International Journal of Endocrinology 2018 (2018): 1–15. http://dx.doi.org/10.1155/2018/5893514.
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Vascular calcification and bone fragility are common and interrelated health problems that affect chronic kidney disease (CKD) patients. Bone fragility, which leads to higher risk of fracture and mortality, arises from the abnormal bone remodeling and mineralization that are seen in chronic kidney disease. Recently, sclerostin and Dickkopf-related protein 1 were suggested to play a significant role in CKD-related bone disease as they are known inhibitors of the Wnt pathway, thus preventing bone formation. This review focuses on new knowledge about the Wnt pathway in bone, how its function is affected by chronic kidney disease and how this affects bone structure. Expression of components and inhibitors of the Wnt pathway has been shown to be affected by the loss of kidney function, and a better understanding of the bone effects of Wnt pathway inhibitors could allow the development of new therapies to prevent bone fragility in this population.