Effect of reproductive hormones on ovarian epithelial tumors: I. Effect on cell cycle activity.
We examined the effects of the 4 major female reproductive hormones, estradiol (E2), progesterone (P4), follicle stimulating hormone (FSH), and luteinizing hormone (LH) on thymidine incorporation in benign and malignant ovarian epithelial tumors cultured in vitro. Treatment of these tumors with E2, FSH and LH resulted in increased thymidine incorporation while treatment with P4 inhibited growth as well as thymidine incorporation. The inhibitory effect of progesterone could not be reproduced by treating the cells with ligands for other steroid hormone receptors known to interact with P4 such as the mineralocorticoid and glucocorticoid receptors. All cells lines expressed at least the PR-A isoform of the progesterone receptor. ORG2058, R5020, RU486, and ZK98299 acted as progesterone receptor agonists with regard to their effect on thymidine incorporation. P4 down-regulated cyclin Bl expression and cdkl activity and up-regulated the p21 and p27 proteins. Expression of a reporter gene downstream to an AP-1 responsive element in a plasmid construct transfected into ovarian epithelial tumor cells was induced by P4 and inhibited by RU486. We conclude that P4 inhibits cell cycle activity in ovarian epithelial tumors, in part via down-regulation of the cdkl/cyclin B complex. This inhibitory effect may have therapeutic utility against ovarian epithelial tumors.
Zhou
Hong
H
Department of Pathology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, California 90033, USA.
Luo
Michelle Ping
MP
Schönthal
Axel H
AH
Pike
Malcolm C
MC
Stallcup
Michael R
MR
Blumenthal
Martina
M
Zheng
Wenxin
W
Dubeau
Louis
L
D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D015536:Down-Regulation; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology; D012739:Gonadal Steroid Hormones / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D007986:Luteinizing Hormone / Q000494:pharmacology; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D011374:Progesterone / Q000494:pharmacology; D011965:Receptors, Glucocorticoid / Q000819:agonists; D018161:Receptors, Mineralocorticoid / Q000819:agonists; D011980:Receptors, Progesterone / Q000819:agonists; D013936:Thymidine / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D012739:Gonadal Steroid Hormones; D008024:Ligands; D011965:Receptors, Glucocorticoid; D018161:Receptors, Mineralocorticoid; D011980:Receptors, Progesterone; D018808:Transcription Factor AP-1; D011374:Progesterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D013936:Thymidine