Estradiol 17β and Its Metabolites Stimulate Cell Proliferation and Antagonize Ascorbic Acid-Suppressed Cell Proliferation in Human Ovarian Cancer Cells

Abstract

Estradiol 17β (E₂β) and ascorbic acid (AA) have been implicated in cancer progression. However, little is known about the actions of biologically active metabolites of E₂β, 2-hydroxyestradiol (2OHE₂), 4-hydroxyestradiol (4OHE₂), 2-methoxyestradiol (2ME₂), and 4-methoxyestradiol (4ME₂) synthesized sequentially by cytochrome P450, family 1, subfamily A (CYP1A1) and B (CYP1B1), polypeptide 1, and catechol-O-methyltransferase (COMT) on ovarian cancer. Herein, we examined the expression of CYP1A1, CYP1B1, COMT, and estrogen receptor α (ERα) and β (ERβ) in human ovarian surface epithelial (IOSE-385) and cancer cell lines (OVCAR-3, SKOV-3, and OVCA-432). We also investigated the roles of E₂β, 2OHE₂, 4OHE₂, 2ME₂, and 4ME₂ in cell proliferation, and their interactive effects with AA on ovarian cells. We found the expression of CYP1A1, CYP1B1, COMT, ERα, and ERβ in most cell lines tested. Treating cells with physiological concentrations of E₂β and its metabolites promoted (13%-42% of the control) IOSE-385 and OVCAR-3 proliferation. The ER blockade inhibited IOSE-385 (∼76%) and OVCAR-3 (∼87%) proliferative response to E₂β but not to its metabolites. The ERα blockade inhibited (∼85%) E₂β-stimulated OVCAR-3 proliferation, whereas ERβ blockade attenuated (∼83%) E₂β-stimulated IOSE-385 proliferation. The AA at ≥250 μmol/L completely inhibited serum-stimulated cell proliferation in all cell lines tested; however, such inhibition in IOSE-385, OVCAR-3, and OVCA-432 was partially (∼10%-20%) countered by E₂β and its metabolites. Thus, our findings indicate that E₂β and its metabolites promote cell proliferation and antagonize the AA-suppressed cell proliferation in a subset of ovarian cancer cells, suggesting that blocking the actions of E₂β and its metabolites may enhance AA’s antiovarian cancer activity.