Cyclooxygenase-2 Inhibitor, Celecoxib, Inhibits Leiomyoma Cell Proliferation Through the Nuclear Factor κB Pathway

Our aim was to investigate whether celecoxib, a cyclooxygenase 2 (COX-2) inhibitor, decreases the in vitro proliferation of leiomyoma cells if the inflammatory pathway is blocked. Menstruation is an inflammation of uterus that produces cytokines and prostanoids, but the inflammatory mechanism underlying the growth of leiomyoma remains unexplained. Using in vitro cultures of leiomyoma cells obtained from 5 patients who underwent hysterectomy, cell proliferation, inflammatory signaling, transcription factors, growth factors, and extracellular matrix were examined by (4,5-dimethylthiaxol-2-yi)-2,5-diphenyltetraxolium bromide assay, immunoblotting, and quantitative polymerase chain reaction. Prostaglandin E2 was used to induce menstruation-like condition in the cells. We found that celecoxib inhibited COX-2 through the expression of nuclear factor κB in the cells. Celcoxib also decreased the gene expression of interleukin 6, tumor necrosis factor α, collagen A, fibronectin, platelet-derived growth factor, epidermal growth factor, and transforming growth factor β. In conclusion, the present study indicated that celecoxib could inhibit leiomyoma cell proliferation through blocking the inflammatory pathway that is probably one of the mechanisms underlying its pathogenesis. Similar content being viewed by others

Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003; 188(1):100–107. Wegienka G, Baird DD, Hertz-Picciotto I, et al. Self-reported heavy bleeding associated with uterine leiomyomata. Obstet Gynecol. 2003;101(3):431–437. Walker CL, Stewart EA. Uterine fibroids: the elephant in the room. Science. 2005;308(5728):1589–1592. Wegienka G. Are uterine leiomyoma a consequence of a chronically inflammatory immune system? Med Hypotheses. 2012; 79(2):226–231. Sikorski R, Kapec E, Zaleska W. Serum levels of proinflammatory cytokines in women with uterine myomas[in Polish]. Ginekol Pol. 2001;72(12A):1485–1488. Gmyrek GB, Sozanski R, Jerzak M, et al. Evaluation of monocyte chemotactic protein-1 levels in peripheral blood of infertile women with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2005;122(2):199–205. Subbaramaiah K, Dannenberg AJ. Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci. 2003;24(2):96–102. Hull MA, Ko SC, Hawcroft G. Prostaglandin EP receptors: targets for treatment and prevention of colorectal cancer? Mol Cancer Ther. 2004;3(8):1031–1039. Lai TY, Chen LM, Lin JY, et al. 17beta-estradiol inhibits prostaglandin E2-induced COX-2 expressions and cell migration by suppressing Akt and ERK1/2 signaling pathways in human LoVo colon cancer cells. Mol Cell Chem. 2010;342(1–2):63–70. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994;107(4):1183–1188. Oshima M, Dinchuk JE, Kargman SL, et al. Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell. 1996;87(5):803–809. Gee J, Lee IL, Jendiroba D, Fischer SM, Grossman HB, Sabichi AL. Selective cyclooxygenase-2 inhibitors inhibit growth and induce apoptosis of bladder cancer. Oncol Rep. 2006;15(2):471–477. Cui W, Yu CH, Hu KQ. In vitro and in vivo effects and mechanisms of celecoxib-induced growth inhibition of human hepatocellular carcinoma cells. Clin Cancer Res. 2005;11(22):8213–8221. Ke X, Dou F, Cheng Z, et al. High expression of cyclooxygenase-2 in uterine fibroids and its correlation with cell proliferation. Eur J Obstet Gynecol Reprod Biol. 2013;168(2):199–203. Downie J, Poyser NL, Wunderlich M. Levels of prostaglandins in human endometrium during the normal menstrual cycle. J Physiol. 1974;236(2):465–472. Han M, Kim JY, Park JE, Kim JM, Lee KS. Effects of letrozole on proliferation and apoptosis in cultured leiomyoma cells treated with prostaglandin E(2). Eur J Obstet Gynecol Reprod Biol. 2008;138(1):83–88. Maruo T, Ohara N, Wang J, Matsuo H. Sex steroidal regulation of uterine leiomyoma growth and apoptosis. Hum Reprod Update. 2004;10(3):207–220. Hoekstra AV, Sefton EC, Berry E, et al. Progestins activate the AKT pathway in leiomyoma cells and promote survival. J Clin Endocrinol Metab. 2009;94(5):1768–1774. Hardy DB, Janowski BA, Corey DR, Mendelson CR. Progesterone receptor plays a major antiinflammatory role in human myometrial cells by antagonism of nuclear factor-kappaB activation of cyclooxygenase 2 expression. Mol Endocrinol. 2006; 20(11):2724–2733. Ninomiya I, Nagai N, Oyama K, et al. Antitumor and anti-metastatic effects of cyclooxygenase-2 inhibition by celecoxib on human colorectal carcinoma xenografts in nude mouse rectum. Oncol Rep. 2012;28(3):777–784. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol. 2000; 18:621–663. Catalano RD, Wilson MR, Boddy SC, Jabbour HN. Comprehensive expression analysis of prostanoid enzymes and receptors in the human endometrium across the menstrual cycle. Mol Hum Reprod. 2011;17(3):182–192. Maybin JA, Hirani N, Jabbour HN, Critchley HO. Novel roles for hypoxia and prostaglandin E2 in the regulation of IL-8 during endometrial repair. Am J Pathol. 2011;178(3): 1245–1256. Peluffo MC, Young KA, Hennebold JD, Stouffer RL. Expression and regulation of tumor necrosis factor (TNF) and TNF-receptor family members in the macaque corpus luteum during the menstrual cycle. Mol Reprod Dev. 2009;76(4):367–378. Sadowsky DW, Adams KM, Gravett MG, Witkin SS, Novy MJ. Preterm labor is induced by intraamniotic infusions of interleukin-1beta and tumor necrosis factor-alpha but not by interleukin-6 or interleukin-8 in a nonhuman primate model. Am J Obstet Gynecol. 2006;195(6):1578–1589. Condon JC, Hardy DB, Kovaric K, Mendelson CR. Up-regulation of the progesterone receptor (PR)-C isoform in laboring myome-trium by activation of nuclear factor-kappaB may contribute to the onset of labor through inhibition of PR function. Mol Endocrinol. 2006;20(4):764–775. Li YF, Xu XB, Chen XH, Wei G, He B, Wang JD. The nuclear factor-kappaB pathway is involved in matrix metalloproteinase-9 expression in RU486-induced endometrium breakdown in mice. Hum Reprod. 2012;27(7):2096–2106. Flake GP, Moore AB, Flagler N, et al. The natural history of uterine leiomyomas: morphometric concordance with concepts of interstitial ischemia and inanosis. Obstet Gynecol Int. 2013; 2013:285103. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Park, S.B., Jee, B.C., Kim, S.H. et al. Cyclooxygenase-2 Inhibitor, Celecoxib, Inhibits Leiomyoma Cell Proliferation Through the Nuclear Factor κB Pathway. Reprod. Sci. 21, 1187–1195 (2014). https://doi.org/10.1177/1933719114542010 Published: Issue date: DOI: https://doi.org/10.1177/1933719114542010