Estradiol 17? and its metabolites stimulate cell proliferation and antagonize ascorbic Acid-suppressed cell proliferation in human ovarian cancer cells.
Estradiol 17? (E2?) and ascorbic acid (AA) have been implicated in cancer progression. However, little is known about the actions of biologically active metabolites of E2?, 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 ? (ER?) and ? (ER?) in human ovarian surface epithelial (IOSE-385) and cancer cell lines (OVCAR-3, SKOV-3, and OVCA-432). We also investigated the roles of E2?, 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, ER?, and ER? in most cell lines tested. Treating cells with physiological concentrations of E2? 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 E2? but not to its metabolites. The ER? blockade inhibited (?85%) E2?-stimulated OVCAR-3 proliferation, whereas ER? blockade attenuated (?83%) E2?-stimulated IOSE-385 proliferation. The AA at ?250 ?mol/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 E2? and its metabolites. Thus, our findings indicate that E2? 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 E2? and its metabolites may enhance AAs antiovarian cancer activity.