Oxidative Stress And The Ovarian Surface Epithelium: Tgf-Beta 1 Stimulation Of Iose Cell Lines Reveals Novel Upregulation Of Nadph Oxidase 4, A Membrane Bound Hydrogen Peroxide Producing Enzyme

Abstract Normal ovarian surface epithelium (OSE) has been widely studied as the origin of ovarian cancer. Repetitive ovulation has been implicated in cancer initiation based on damage and inflammation incurred to the OSE upon continuous cycles of tear and repair. Transforming growth factor-beta (TGF-β) plays a role in this normal ovulatory cycle, having been shown to inhibit human OSE proliferation and induce apoptosis, which may prevent the over-proliferation of cells. NADPH oxidase 4 (NOX4), a membrane-associated hydrogen peroxide-producing enzyme, has previously been shown to be sensitive to TGF-β1, with increased expression stimulated in smooth muscle cells and fibroblasts. Here we describe for the first time TGF-β1 induced upregulation of NOX4 in immortalized OSE (IOSE) cells (IOSE121, IOSE144, IOSE364, IOSE386 and IOSE397). This time-dependent increased expression (>5 fold at 2 ng/ml TGF-β1, 24 h) was simulated by direct overexpression of NOX4 in IOSE397 cells and has demonstrated that increased NOX4, in the absence of further growth factor related effects, affords induction of p18 and p21. In addition, using immunohistochemical evaluation of human ovarian cancers in tissue microarrays (n=17 patients), we observed significantly increased expression of NOX4, suggesting that NOX4 upregulation may contribute to the malignant transformation of ovarian cells. Citation Format: Jennifer L. Meitzler, Becky A. Diebold, Smitha Antony, Yongzhong Wu, Agnes Juhasz, Iris Dahan, Guojian Jiang, Jiamo Lu, Stephen Wang, Mariam M. Konaté, Krishnendu Roy, James H. Doroshow. Oxidative stress and the ovarian surface epithelium: TGF-β1 stimulation of IOSE cell lines reveals novel upregulation of NADPH oxidase 4, a membrane bound hydrogen peroxide producing enzyme [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3571.