Similar articles

Abstract: Objective: Drug-resistance and metastasis are major reasons for the high mortality of ovarian cancer (OC) patients. cyclooxygenase-2 (COX-2) plays a critical role in OC development. This study was designed to evaluate the effects of COX-2 on migration and cisplatin (cis-dichloro diammine platinum, CDDP) resistance of OC cells and explore its related mechanisms. Methods: Cell counting kit-8 (CCK-8) assay was used to detect the cytotoxicity effects of celecoxib (CXB) and CDDP on SKOV3 and ES2 cells. The effect of COX-2 on migration was evaluated via the healing test. Western blot and real-time quantitative polymerase chain reaction (qPCR) were used to analyze E-cadherin, vimentin, Snail, and Slug levels. Results: COX-2 promoted drug-resistance and cell migration. CXB inhibited these effects. The combination of CDDP and CXB increased tumor cell sensitivity, reduced the amount of CDDP required, and shortened treatment administration time. COX-2 upregulation increased the expression of Snail and Slug, resulting in E-cadherin expression downregulation and vimentin upregulation. Conclusions: COX-2 promotes cancer cell migration and CDDP resistance and may serve as a potential target for curing OC.

环氧合酶-2(COX-2)通过调控细胞上皮间质转化(EMT)促进卵巢癌细胞迁移及其耐药性

[1]JNCI (Journal of the National Cancer Institute), 2011. Ovarian cancer, five-year stage-specific relative survival rates (2004–2008). J Natl Cancer Inst, 103(17):1287.

[2]al-Wadei HAN, al-Wadei MH, Ullah MF, et al., 2012. Celecoxib and GABA cooperatively prevent the progression of pancreatic cancer in vitro and in xenograft models of stress-free and stress-exposed mice. PLoS ONE, 7(8):e43376.

[3]Barnes AP, Miller BE, Kucera GL, 2007. Cyclooxygenase inhibition and hyperthermia for the potentiation of the cytotoxic response in ovarian cancer cells. Gynecol Oncol, 104(2):443-450.

[4]Bertagnolli MM, Eagle CJ, Zauber AG, et al., 2009. Five-year efficacy and safety analysis of the adenoma prevention with celecoxib trial. Cancer Prev Res, 2(4):310-321.

[5]Buys SS, Partridge E, Black A, et al., 2011. Effect of screening on ovarian cancer mortality: the prostate, lung, colorectal and ovarian (PLCO) cancer screening randomized controlled trial. JAMA, 305(22):2295-2303.

[6]Cervello M, Bachvarov D, Lampiasi N, et al., 2013. Novel combination of sorafenib and celecoxib provides synergistic anti-proliferative and pro-apoptotic effects in human liver cancer cells. PLoS ONE, 8(6):e65569.

[7]Chen FL, Wen X, Lin PF, et al., 2019. HERP depletion inhibits zearalenone-induced apoptosis through autophagy activation in mouse ovarian granulosa cells. Toxicol Lett, 301: 1-10.

[8]Chen MHS, Yip GWC, Tse GMK, et al., 2008. Expression of basal keratins and vimentin in breast cancers of young women correlates with adverse pathologic parameters. Mod Pathol, 21(10):1183-1191.

[9]Chen XL, Lingala S, Khoobyari S, et al., 2011. Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations. J Hepatol, 55(4):838-845.

[10]Cho EY, Choi Y, Chae SW, et al., 2006. Immunohistochemical study of the expression of adhesion molecules in ovarian serous neoplasms. Pathol Int, 56(2):62-70.

[11]Chung LY, Tang SJ, Sun GH, et al., 2012. Galectin-1 promotes lung cancer progression and chemoresistance by upregulating p38 MAPK, ERK, and cyclooxygenase-2. Clin Cancer Res, 18(15):4037-4047.

[12]Denkert C, Fürstenberg A, Daniel PT, et al., 2003. Induction of G0/G1 cell cycle arrest in ovarian carcinoma cells by the anti-inflammatory drug NS-398, but not by COX-2-specific RNA interference. Oncogene, 22(54):8653-8661.

[13]Denkert C, Weichert W, Pest S, et al., 2004. Overexpression of the embryonic-lethal abnormal vision-like protein HuR in ovarian carcinoma is a prognostic factor and is associated with increased cyclooxygenase 2 expression. Cancer Res, 64(1):189-195.

[14]Ferrandina G, Lauriola L, Distefano MG, et al., 2002. Increased cyclooxygenase-2 expression is associated with chemotherapy resistance and poor survival in cervical cancer patients. J Clin Oncol, 20(4):973-981.

[15]Ferrandina G, Zannoni GF, Ranelletti FO, et al., 2004. Cyclooxygenase-2 expression in borderline ovarian tumors. Gynecol Oncol, 95(1):46-51.

[16]Gartung A, Yang J, Sukhatme VP, et al., 2019. Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor. Proc Natl Acad Sci USA, 116(5):1698-1703.

[17]Giaginis C, Alexandrou P, Tsoukalas N, et al., 2015. Hu-antigen receptor (HuR) and cyclooxygenase-2 (COX-2) expression in human non-small-cell lung carcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients’ survival. Tumour Biol, 36(1):315-327.

[18]Harris RE, Casto BC, Harris ZM, 2014. Cyclooxygenase-2 and the inflammogenesis of breast cancer. World J Clin Oncol, 5(4):677-692.

[19]Hu Z, Liu XJ, Tang ZF, et al., 2013. Possible regulatory role of Snail in NF-κB-mediated changes in E-cadherin in gastric cancer. Oncol Rep, 29(3):993-1000.

[20]Jemal A, Siegel R, Xu JQ, et al., 2010. Cancer statistics, 2010. CA Cancer J Clin, 60(5):277-300.

[21]Kim HJ, Yim GW, Nam EJ, et al., 2014. Synergistic effect of COX-2 inhibitor on paclitaxel-induced apoptosis in the human ovarian cancer cell line OVCAR-3. Cancer Res Treat, 46(1):81-92.

[22]Kısmet K, Akay MT, Abbasoglu O, et al., 2004. Celecoxib: a potent cyclooxygenase-2 inhibitor in cancer prevention. Cancer Detect Prev, 28(2):127-142.

[23]Konstan MW, Byard PJ, Hoppel CL, et al., 1995. Effect of high-dose ibuprofen in patients with cystic fibrosis. N Engl J Med, 332(13):848-854.

[24]Koti M, Siu A, Clément I, et al., 2015. A distinct pre-existing inflammatory tumour microenvironment is associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer. Br J Cancer, 112(7):1215-1222.

[25]Landen CN Jr, Mathur SP, Richardson MS, et al., 2003. Expression of cyclooxygenase-2 in cervical, endometrial, and ovarian malignancies. Am J Obstet Gynecol, 188(5):1174-1176.

[26]Legge F, Paglia A, D'Asta M, et al., 2011. Phase II study of the combination carboplatin plus celecoxib in heavily pre-treated recurrent ovarian cancer patients. BMC Cancer, 11:214.

[27]Li SF, Miner K, Fannin R, et al., 2004. Cyclooxygenase-1 and 2 in normal and malignant human ovarian epithelium. Gynecol Oncol, 92(2):622-627.

[28]Li SS, Ma J, Wong AST, 2018. Chemoresistance in ovarian cancer: exploiting cancer stem cell metabolism. J Gynecol Oncol, 29(2):e32.

[29]Madan RA, Xia Q, Chang VT, et al., 2007. A retrospective analysis of cardiovascular morbidity in metastatic hormone-refractory prostate cancer patients on high doses of the selective COX-2 inhibitor celecoxib. Expert Opin Pharmacother, 8(10):1425-1431.

[30]Neumann W, Crews BC, Sárosi MB, et al., 2015. Conjugation of cisplatin analogues and cyclooxygenase inhibitors to overcome cisplatin resistance. ChemMedChem, 10(1):183-192.

[31]Okamura H, Fujiwara H, Umehara S, et al., 2013. COX-2 overexpression induced by gene transfer reduces sensitivity of TE13 esophageal carcinoma cells to 5-fluorouracil and cisplatin. Anticancer Res, 33(2):537-542.

[32]Raspollini MR, Amunni G, Villanucci A, et al., 2005. Increased cyclooxygenase-2 (COX-2) and p-glycoprotein-170 (MDR1) expression is associated with chemotherapy resistance and poor prognosis. Analysis in ovarian carcinoma patients with low and high survival. Int J Gynecol Cancer, 15(2):255-260.

[33]Sangoi AR, Soslow RA, Teng NN, et al., 2008. Ovarian clear cell carcinoma with papillary features: a potential mimic of serous tumor of low malignant potential. Am J Surg Pathol, 32(2):269-274.

[34]Shigemasa K, Tian X, Gu L, et al., 2003. Expression of cyclooxygenase-2 and its relationship to p53 accumulation in ovarian adenocarcinomas. Int J Oncol, 22(1):99-105.

[35]Soslow RA, Dannenberg AJ, Rush D, et al., 2000. COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer, 89(12):2637-2645.

[36]Subbaramaiah K, Hart JC, Norton L, et al., 2000. Microtubule-interfering agents stimulate the transcription of cyclooxygenase-2. Evidence for involvement of ERK1/2 and p38 mitogen-activated protein kinase pathways. J Biol Chem, 275(20):14838-14845.

[37]Wei J, Xu G, Wu M, et al., 2008. Overexpression of vimentin contributes to prostate cancer invasion and metastasis via SRC regulation. Anticancer Res, 28(1A):327-334.

[38]Yim GW, Kim HJ, Kim LK, et al., 2017. Long non-coding RNA HOXA11 antisense promotes cell proliferation and invasion and predicts patient prognosis in serous ovarian cancer. Cancer Res Treat, 49(3):656-668.

[39]Zhai XL, Zhu HJ, Wang W, et al., 2014. Abnormal expression of EMT-related proteins, S100A4, vimentin and E-cadherin, is correlated with clinicopathological features and prognosis in HCC. Med Oncol, 31(6):970.

[40]Zhang RR, Zhang P, Wang H, et al., 2015. Inhibitory effects of metformin at low concentration on epithelial-mesenchymal transition of CD44⁺CD117⁺ ovarian cancer stem cells. Stem Cell Res Ther, 6(1):262.

[41]Zhao Y, Yan QM, Long X, et al., 2008. Vimentin affects the mobility and invasiveness of prostate cancer cells. Cell Biochem Funct, 26(5):571-577.