PROGESTERONE INDUCES APOPTOSIS AND UP-REGULATION OF P53 EXPRESSION INHUMAN OVARIAN-CARCINOMA CELL-LINES

BACKGROUND. Progesterone (FROG) has been shown to reduce the risk of d eveloping ovarian carcinoma in postmenopausal women who have undergone estrogen and progestogen replacement therapy, and it has been clinica lly used to treat some types of ovarian tumors. It is not yet clear wh ether or not the antitumor activity of progestogen is due to its abili ty to induce apoptosis in precarcinomatous and carcinomatous ovarian c ells. The apoptosis-related genes p53, bcl-2, and c-myc have important roles in the regulation of programmed cell death, and thus may be inv olved in the process of the suspected FROG-induced apoptosis. METHODS. Antiproliferation effects of FROG on 3AO and AO ovarian carcinoma cel ls were determined by H-3-thymidine incorporation. Apoptosis of the PR OG-treated cells was determined by DNA laddering analysis and was quan titated by both nuclear condensation and flow cytometry after cells we re stained with propidium iodide. Cell cycle analysis was also perform ed by flow cytometry. The expression of p53, bcl-2, and c-myc after 72 hours of FROG treatment was detected by Northern blot analysis. RESUL TS. In both 3AO and AO cell lines, cells proliferation was maximally i nhibited by FROG after 72 hours of treatment at 10 mu M concentration. Under the same conditions, more than 50% of FROG-treated cells had un dergone apoptosis, whereas less than 3% of the cells were apoptotic in untreated cell cultures. After exposure to FROG for 72 hours, cells w ere arrested in the GI phase of the cell cycle, and the levels of p53 mRNA were remarkably increased in both cell lines. No changes in expre ssion of bcl-2 or c-myc were detected. CONCLUSIONS. FROG significantly inhibited cell proliferation and induced apoptosis in both of the ova rian carcinoma cell lines tested in this study. FROG treatment markedl y up-regulated p53 expression in these cells, indicating involvement o f p53 in FROG-induced apoptosis. (C) 1997 American Cancer Society.