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Academic literature on the topic 'Prostaglandin E2, nuclear EGFR, lung cancer'
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Journal articles on the topic "Prostaglandin E2, nuclear EGFR, lung cancer"
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Lin, Chih-Chung, I.-Ta Lee, Wan-Ling Wu, Wei-Ning Lin, and Chuen-Mao Yang. "Adenosine triphosphate regulates NADPH oxidase activity leading to hydrogen peroxide production and COX-2/PGE2 expression in A549 cells." American Journal of Physiology-Lung Cellular and Molecular Physiology 303, no. 5 (September 1, 2012): L401—L412. http://dx.doi.org/10.1152/ajplung.00090.2012.
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Non-small cell lung carcinoma (NSCLC) accounts for most of all lung cancers, which is the leading cause of mortality in human beings. High level of cyclooxygenase-2 (COX-2) is one of the features of NSCLC and related to the low survival rate of NSCLC. However, whether extracellular nucleotides releasing from stressed resident tissues contributes to the expression of COX-2 remains unclear. Here, we showed that stimulation of A549 cells by adenosine 5′- O-(3-thiotriphosphate) (ATPγS) led to an increase in COX-2 gene expression and prostaglandin E2 (PGE2) synthesis, revealed by Western blotting, RT-PCR, promoter assay, and enzyme-linked immunosorbent assay. In addition, ATPγS induced intracellular reactive oxygen species (ROS) generation through the activation of NADPH oxidase. The increase of ROS level resulted in activation of the c-Src/epidermal growth factor receptor (EGFR)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/nuclear factor (NF)-κB cascade. We also found that activated Akt was translocated into the nucleus and recruited with NF-κB and p300 to form a complex. Thus, activation of p300 modulated the acetylation of histone H4 via the NADPH oxidase/c-Src/EGFR/PI3K/Akt/NF-κB cascade stimulated by ATPγS. Our results are the first to show a novel role of NADPH oxidase-dependent Akt/p65/p300 complex formation that plays a key role in regulating COX-2/PGE2 expression in ATPγS-treated A549 cells. Taken together, we demonstrated that ATPγS stimulated activation of NADPH oxidase, resulting in generation of ROS, which then activated the downstream c-Src/EGFR/PI3K/Akt/NF-κB/p300 cascade to regulate the expression of COX-2 and synthesis of PGE2 in A549 cells. Understanding the regulation of COX-2 expression and PGE2 release by ATPγS on A549 cells may provide potential therapeutic targets of NSCLC.
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Martey, Christine A., Stephen J. Pollock, Chantal K. Turner, Katherine M. A. O'Reilly, Carolyn J. Baglole, Richard P. Phipps, and Patricia J. Sime. "Cigarette smoke induces cyclooxygenase-2 and microsomal prostaglandin E2 synthase in human lung fibroblasts: implications for lung inflammation and cancer." American Journal of Physiology-Lung Cellular and Molecular Physiology 287, no. 5 (November 2004): L981—L991. http://dx.doi.org/10.1152/ajplung.00239.2003.
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Cigarette smoking can lead to many human pathologies including cardiovascular and respiratory disease. Recent studies have defined a role for fibroblasts in the development of colon cancer. Moreover, fibroblasts are now thought of as key “sentinel” cells that initiate inflammation by releasing proinflammatory mediators including prostaglandins (PGs). Pathological overexpression of cyclooxygenase-2 (COX-2) and excess eicosanoid production are found in the early stages of carcinogenesis. By promoting chronic inflammation, COX-2 and eicosanoid production may actually cause a predisposition to malignancy. Furthermore, the associated inflammation induced by production of these mediators is central to the pathogenesis of chronic obstructive pulmonary disease. Little is known of the responses of normal lung fibroblasts to cigarette smoke, despite their abundance. We report herein that normal human lung fibroblasts, when exposed to cigarette smoke extract, induce COX-2 with concurrent synthesis of prostaglandin E2 (PGE2). The mechanisms by which cigarette-derived toxicants lead to increased COX-2 levels and PGE2 synthesis include increases in steady-state COX-2 mRNA levels (approximately four- to fivefold), phosphorylation of ERK1/2, and nuclear translocation of the p50 and p65 subunits of the transcription factor NF-κB, which are important elements in COX-2 expression. Furthermore, there was a dramatic 25-fold increase in microsomal prostaglandin E synthase, the key enzyme involved in the production of PGE2. We propose that normal human lung fibroblasts, when exposed to cigarette smoke constituents, elicit COX-2 expression with consequent prostaglandin synthesis, thus creating a proinflammatory environment. This chronic inflammatory state may act as one of the first steps towards epithelial transformation.
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Reckamp, K. L., J. Czernin, W. A. Weber, S. M. Dubinett, and R. A. Figlin. "Targeted COX-2 and EGFR TK inhibition in advanced non-small cell lung cancer." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 7179. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.7179.
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7179 Background: Prostaglandin E2 (PGE2) activates Erk/MAPK signaling pathway in an epidermal growth factor receptor (EGFR) tyrosine kinase (TK)-resistant manner as a result of cyclooxygenase-2 (COX-2) overexpressed in lung cancer. Because 10% of patients respond to this class of drugs, evaluating agents that may overcome resistance and determining the population of patients most likely to respond is crucial. Imaging tumor metabolism by positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) is an innovative approach for assessing the efficacy of targeted agents. We studied the combination of COX-2 inhibition (celecoxib) and EGFR inhibition (erlotinib) in a phase I trial in advanced non-small cell lung cancer (NSCLC) and added FDG-PET imaging as a potential method for evaluation of early response. Methods: A phase I, dose escalation trial to investigate the optimal biologic dose (OBD) of the combination of celecoxib and erlotinib in pts with refractory stage IIIB/IV NSCLC. FDG-PET was evaluated in selected patients at baseline, week 2 and week 8 of study treatment. Tumor metabolic activity was quantitatively assessed by standardized uptake values (SUV). Changes in SUV were compared to CT imaging at week 8 with response defined by RECIST criteria. Results: Twenty-two subjects were enrolled and 21 were evaluable for the determination of the OBD, toxicity assessment and response. Rash and skin-related effects were the most commonly reported toxicities. Seven patients demonstrated partial responses and five patients developed stable disease. Responses were seen in patients both with and without EGFR activating mutations. The duration of partial response was 24–93 wks. TTP was 83 weeks in one patient with stable disease. A patient evaluated by FDG-PET had a significant decrease in SUV (-45%) at week 2 which corresponded to partial responses by RECIST at week 8. Conclusions: FDG-PET as a measure of tumor glucose utilization appears to be a promising tool for assessing early response to targeted therapies. A randomized Phase II trial is planned comparing erlotinib and celecoxib with erlotinib plus placebo in advanced NSCLC, and evaluating FDG-PET response as a marker of early efficacy. Supported by UCLA Lung Cancer SPORE NCI P50 CA 90388, GLAVAHS CDA and STOP Cancer Award. [Table: see text]
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Martey, C. A., C. J. Baglole, T. A. Gasiewicz, P. J. Sime, and R. P. Phipps. "The aryl hydrocarbon receptor is a regulator of cigarette smoke induction of the cyclooxygenase and prostaglandin pathways in human lung fibroblasts." American Journal of Physiology-Lung Cellular and Molecular Physiology 289, no. 3 (September 2005): L391—L399. http://dx.doi.org/10.1152/ajplung.00062.2005.
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Cigarette smoking can lead to chronic lung inflammation and lung cancer. Chronic inflammation, associated with expression of cyclooxygenase-2 (COX-2) and prostaglandins, predisposes to malignancy. We recently demonstrated that human lung fibroblasts are activated by cigarette smoke to express COX-2 and prostaglandin E2 (PGE2). Little is known about the mechanism whereby smoke activates human lung fibroblasts to produce proinflammatory mediators. Herein, we report the central role of the aryl hydrocarbon receptor (AHR) in cigarette smoke extract (CSE)-induced COX-2, microsomal PGE2 synthase (mPGES), and PGE2 production in human lung fibroblasts. Western blot analysis revealed that primary strains of human lung fibroblasts express AHR and aryl hydrocarbon nuclear translocator protein, supporting the possibility that smoke activates lung fibroblasts through this pathway. Experiments were subsequently performed to determine whether the AHR was activated by CSE. Immunocytochemistry and EMSA analysis revealed that CSE induced nuclear translocation of the AHR in human lung fibroblasts. CSE decreased protein levels of the AHR, consistent with AHR ligand-induced proteosome-mediated degradation. CSE also induced mPGES-1 and COX-2 protein and increased PGE2 production. Treatment of human fibroblasts with AHR antagonists in the presence of CSE inhibited AHR nuclear translocation as well as COX-2, mPGES-1, and PGE2 production. These data indicate that the AHR pathway plays an important role in cigarette smoke-mediated COX-2 and PG production in human lung fibroblasts and may contribute to tobacco-associated inflammation and lung disease.
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Reckamp, K. L., B. K. Gardner, R. A. Figlin, D. Elashoff, K. Krysan, M. Dohadwala, L. Inge, A. Rajasekaran, and S. M. Dubinett. "Decline in serum soluble E-cadherin and low baseline matrix metalloproteinase-9 are associated with response to combination celecoxib and erlotinib therapy in advanced non-small cell lung cancer." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 7640. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7640.
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7640 Background: Cyclooxygenase-2 (COX-2) overexpression may mediate resistance to EGFR TK inhibition through prostaglandin E2 (PGE2)-dependent promotion of epithelial to mesenchymal transition (EMT). Thomson, et al. reported that the suppression of epithelial markers such as E-cadherin led to resistance to erlotinib (Cancer Res 2005;65:9455). In addition, PGE2 downregulates E-cadherin expression by upregulating transcriptional repressors including ZEB1 and Snail, as described by Dohadwala et al (Cancer Res 2006;66:5338). These findings suggest that COX-2 inhibition may enhance the efficacy of EGFR TKI therapy in NSCLC. Methods: A phase I, dose escalation trial to was performed investigating the combination of celecoxib and erlotinib in pts with advanced NSCLC. Soluble E-cadherin (sEC) was evaluated by ELISA in pt serum at baseline and weeks 4 and 8 of treatment. Other markers of COX-2 gene expression were evaluated by ELISA, including matrix metalloproteinase (MMP)-9, MMP-2 and tissue inhibitor of MMP (TIMP1). Results: 22 pts were enrolled and 21 were evaluable for the determination of the optimal dose, toxicity assessment and response (reported in Clin Cancer Res 2006;12:3381). Here we report serum sEC and MMP-9 levels, which were analyzed according to best response (PR, SD or PD) in 21 pts. SEC was analyzed according to best response (PR, SD or PD). We found a significant decrease in sEC between baseline and week 8 in pts with PR when compared to those with SD or PD (p = 0.021). In pts who responded to the combination therapy, baseline MMP-9 was significantly lower compared to non-responders (p = 0.006). Conclusions: SEC, MMP-9 and other downstream markers of COX-2 gene expression may be useful for assessing response to combination celecoxib and erlotinib in pts with advanced NSCLC. A randomized Phase II trial is planned comparing erlotinib and celecoxib with erlotinib plus placebo in advanced NSCLC, to evaluate the efficacy of this combination therapy and to assess these and other biomarkers in both serum and tumor tissue. Supported by ASCO Young Investigator Award, UCLA Lung Cancer SPORE NCI P50 CA 90388 and GLAVAHS Career Development Award. No significant financial relationships to disclose.
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Zheng, Yu, Valentine Comaills, Risa Burr, Gaylor Boulay, David T. Miyamoto, Ben S. Wittner, Erin Emmons, et al. "COX-2 mediates tumor-stromal prolactin signaling to initiate tumorigenesis." Proceedings of the National Academy of Sciences 116, no. 12 (February 28, 2019): 5223–32. http://dx.doi.org/10.1073/pnas.1819303116.
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Tumor-stromal communication within the microenvironment contributes to initiation of metastasis and may present a therapeutic opportunity. Using serial single-cell RNA sequencing in an orthotopic mouse prostate cancer model, we find up-regulation of prolactin receptor as cancer cells that have disseminated to the lungs expand into micrometastases. Secretion of the ligand prolactin by adjacent lung stromal cells is induced by tumor cell production of the COX-2 synthetic product prostaglandin E2 (PGE2). PGE2 treatment of fibroblasts activates the orphan nuclear receptor NR4A (Nur77), with prolactin as a major transcriptional target for the NR4A-retinoid X receptor (RXR) heterodimer. Ectopic expression of prolactin receptor in mouse cancer cells enhances micrometastasis, while treatment with the COX-2 inhibitor celecoxib abrogates prolactin secretion by fibroblasts and reduces tumor initiation. Across multiple human cancers, COX-2, prolactin, and prolactin receptor show consistent differential expression in tumor and stromal compartments. Such paracrine cross-talk may thus contribute to the documented efficacy of COX-2 inhibitors in cancer suppression.
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Monteleone, Nicholas J., and Carol S. Lutz. "miR-708 Negatively Regulates TNFα/IL-1β Signaling by Suppressing NF-κB and Arachidonic Acid Pathways." Mediators of Inflammation 2021 (March 10, 2021): 1–11. http://dx.doi.org/10.1155/2021/5595520.
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Two pathways commonly dysregulated in autoimmune diseases and cancer are tumor necrosis factor alpha (TNFα) and interleukin 1 beta (IL-1β) signaling. Researchers have also shown that both signaling cascades positively regulate arachidonic acid (AA) signaling. More specifically, TNFα/IL-1β promotes expression of the prostaglandin E2- (PGE2-) producing enzymes, cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-1). Exacerbated TNFα, IL-1β, and AA signaling have been associated with many diseases. While some TNFα therapies have significantly improved patients’ lives, there is still an urgent need to develop novel therapeutics that more comprehensively treat inflammatory-related diseases. Recently, researchers have begun to use RNA interference (RNAi) to treat various diseases in the clinic. One type of RNAi is microRNA (miRNA), a class of small noncoding RNA found within cells. One miRNA in particular, miR-708, has been shown to target COX-2 and mPGES-1. Previous studies have also suggested that miR-708 may be a negative regulator of TNFα/IL-1β signaling. Therefore, we studied the relationship between miR-708, TNFα/IL-1β, and AA signaling in diseased lung cells. We found that miR-708 negatively regulates TNFα/IL-1β signaling in nondiseased lung cells, which is lost in diseased lung cells. Transient transfection of miR-708 suppressed TNFα/IL-1β-induced changes in COX-2, mPGES-1, and PGE2 levels. Moreover, miR-708 also suppressed TNFα/IL-1β-induced IL-6 independent of AA signaling. Mechanistically, we determined that miR-708 suppressed IL-6 signaling by reducing expression of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activator inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ). Collectively, our data suggest miR-708 regulates TNFα/IL-1β signaling by inhibiting multiple points of the signaling cascade.
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BAI, XIAOMING, QINYI YANG, WEI SHU, JIE WANG, LI ZHANG, JUAN MA, SHUKAI XIA, et al. "Prostaglandin E2 upregulates β1 integrin expression via the E prostanoid 1 receptor/nuclear factor κ-light-chain-enhancer of activated B cells pathway in non-small-cell lung cancer cells." Molecular Medicine Reports 9, no. 5 (February 28, 2014): 1729–36. http://dx.doi.org/10.3892/mmr.2014.2000.
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Mao, Tsui-Lien, Ming-Huei Fan, Nhlanhla Dlamini, and Chao-Lien Liu. "LncRNA MALAT1 Facilitates Ovarian Cancer Progression through Promoting Chemoresistance and Invasiveness in the Tumor Microenvironment." International Journal of Molecular Sciences 22, no. 19 (September 22, 2021): 10201. http://dx.doi.org/10.3390/ijms221910201.
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Upregulation of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1, also known as nuclear-enriched abundant transcript 2 (NEAT2) or LINC00047) was found in various solid tumors, including epithelial ovarian cancer (EOC). MALAT1 is a long noncoding (lnc)RNA that regulates many functional signaling pathways, including tumorigenesis. Herein, we observed the consistent upregulation of MALAT1 in MYST4-overexpressing cell lines, while MALAT1 was frequently found to be upregulated in various types of clinical carcinoma tissues, especially EOC. To further investigate the lncRNA MALAT1 in EOC progression, the transduced overexpression of MALAT1 in EOC cell lines and cancer-associated fibroblasts (CAFs) was employed. We found that MALAT1 overexpression in EOC cell lines significantly increased drug resistance, cell migration, and invasion. Furthermore, the concomitant overexpression of MALAT1 in EOC cells and CAFs dramatically increased EOC cell invasion. Accordingly, a mechanistic investigation of MALAT1 overexpression in EOC cells showed that expressions of the cytokines interleukin (IL)-1β and p-P38/p-NFκB/Cox2/prostaglandin E2 (PGE2) signaling were significantly increased, which stimulated inflammatory responses, whereas cell apoptosis was inhibited due to increased Bcl-2 levels and reduced Caspase3 levels. After MALAT1 was overexpressed in EOC cells, and the cyclin D1, p-PI3K, and p-Akt expressions increased, suggesting the promotion of tumor cell proliferation, while increased zinc finger E-box-binding homeobox-2 (ZEB2), yes-associated protein (YAP), and vimentin expression with E-cadherin downregulation indicated the enhancement of the epithelial-to-mesenchymal transition (EMT) in terms of metastasis, thereby triggering EOC progression. Together, our findings demonstrate how MALAT1 overexpression facilitates an oncogenic function through inhibiting tumor cell apoptosis, combined with increasing tumor cell inflammation, proliferation, and invasion in the EOC tumor microenvironment. MALAT1 is thus a potential diagnostic marker and therapeutic for this malignancy.
Dissertations / Theses on the topic "Prostaglandin E2, nuclear EGFR, lung cancer"
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BAZZANI, LORENZO. "Prostaglandin E2 promotes EGFR trafficking from cell membrane to the nucleus in human non small cell lung cancer cells." Doctoral thesis, Università di Siena, 2016. http://hdl.handle.net/11365/1004580.
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Lung cancer is the leading cause of cancer-related death with a 5-year survival rate less than 15%. In this heterogeneous disease, Epidermal growth factor receptor (EGFR) is one of the main oncogenic drivers. EGFR plays a critical role in lung cancer development and progression. It is highly expressed and frequently mutated in lung malignancies and correlates with poor prognosis. Monoclonal antibodies and small molecule tyrosine kinase inhibitors targeting EGFR were highly effective drugs for treatment of lung cancer, colorectal cancer and squamous cells head and neck carcinoma. However, despite the initial enthusiasm, almost all of patients develop resistance in 1-2 years post treatment.
In addition to the classical signaling pathways initiated at the cell surface, EGFR has been reported to be translocated into the nucleus and to be involved in the development of an aggressive phenotype and resistance to therapies. Indeed, within the nucleus, EGFR serves as a: i. transcriptional co-activator for a series of genes involved in multiple biological functions, including cell proliferation, tumor progression, DNA repair and replication, chemo and radioresistance; ii. protein kinase and protein-protein interactor.
Chronic inflammation is a critical component of cancer progression and a cross-talk between inflammatory mediators, such as Prostaglandin E2 (PGE2) and EGFR has been reported. The aim of this PhD thesis was to assess whether PGE2 contributes to EGFR nuclear translocation. Lung cancer cell lines (A549, GLC82), representative of tumor with high dependency on EGFR axis, were chosen as a model for the study. Here we provided a breakthrough in the field of GPCR-RTK transactivation highlighting the mechanism of PGE2-induced EGFR nuclear translocation. We found that prostaglandin EP3 receptor promotes shedding of membrane-bound EGF-like ligands via Src family kinases/ADAM proteases leading to EGFR activation and consequent internalization. Upon PGE2 treatment, EGFR undergoes to Clathrin- and Caveolin-mediated endocytosis and associates with Importin β1, which promotes its nuclear import. In the nucleus, we observed that PGE2 drives EGFR interaction with STAT3 leading to transcription of genes such as COX-2, iNOS, c-Myc and cyclin D1, which are known to fuel pro-inflammatory microenvironment and tumor progression.
In conclusion, our findings indicate that PGE2 promotes EGFR nuclear translocation and contributes to sustain its oncogenic drive suggesting pharmacological targeting of PGE2 as a novel strategy for treatment of NSCLC in combination with chemo and targeted therapy.