title: 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.
authors.affiliation: 1Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Shandong, China.
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Li
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Cai-Feng
authors.initials: CF
authors.lastname: Dai
authors.forename: Sheikh O
authors.initials: SO
authors.lastname: Jobe
authors.forename: Xing-Sheng
authors.initials: XS
authors.lastname: Yang
authors.forename: Xing-Fu
authors.initials: XF
authors.lastname: Li
authors.forename: Manish S
authors.initials: MS
authors.lastname: Patankar
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Magness
authors.forename: Jing
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000077584:2-Methoxyestradiol; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001205:Ascorbic Acid / Q000494:pharmacology*; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000187:drug effects / Q000378:metabolism; D002393:Estrogens, Catechol / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors
chemical_list: C506487:ESR1 protein, human; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D002393:Estrogens, Catechol; C045018:4-methoxyestradiol; D004958:Estradiol; D000077584:2-Methoxyestradiol; C001390:2-hydroxyestradiol; C014036:4-hydroxyestradiol; D001189:Aryl Hydrocarbon Hydroxylases; C569463:CYP1A1 protein, human; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; D001205:Ascorbic Acid
keywords: E2β; E2β metabolites; ascorbic acid; growth; ovarian cancer cells