Progesterone induces apoptosis and up-regulation of p53 expression in human ovarian carcinoma cell lines.
BACKGROUND
Progesterone (PROG) has been shown to reduce the risk of developing ovarian carcinoma in postmenopausal women who have undergone estrogen and progestogen replacement therapy, and it has been clinically used to treat some types of ovarian tumors. It is not yet clear whether or not the antitumor activity of progestogen is due to its ability to induce apoptosis in precarcinomatous and carcinomatous ovarian cells. The apoptosis-related genes p53, bcl-2, and c-myc have important roles in the regulation of programmed cell death, and thus may be involved in the process of the suspected PROG-induced apoptosis.


METHODS
Antiproliferation effects of PROG on 3AO and AO ovarian carcinoma cells were determined by 3H-thymidine incorporation. Apoptosis of the PROG-treated cells was determined by DNA laddering analysis and was quantitated by both nuclear condensation and flow cytometry after cells were stained with propidium iodide. Cell cycle analysis was also performed by flow cytometry. The expression of p53, bcl-2, and c-myc after 72 hours of PROG treatment was detected by Northern blot analysis.


RESULTS
In both 3AO and AO cell lines, cells proliferation was maximally inhibited by PROG after 72 hours of treatment at 10 microM concentration. Under the same conditions, more than 50% of PROG-treated cells had undergone apoptosis, whereas less than 3% of the cells were apoptotic in untreated cell cultures. After exposure to PROG for 72 hours, cells were arrested in the G1 phase of the cell cycle, and the levels of p53 mRNA were remarkably increased in both cell lines. No changes in expression of bcl-2 or c-myc were detected.


CONCLUSIONS
PROG significantly inhibited cell proliferation and induced apoptosis in both of the ovarian carcinoma cell lines tested in this study. PROG treatment markedly up-regulated p53 expression in these cells, indicating involvement of p53 in PROG-induced apoptosis.
Bu
S Z
SZ
Shanghai Institute of Cell Biology, Chinese Academy of Sciences.
Yin
D L
DL
Ren
X H
XH
Jiang
L Z
LZ
Wu
Z J
ZJ
Gao
Q R
QR
Pei
G
G
D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015152:Blotting, Northern; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004396:Coloring Agents; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D004587:Electrophoresis, Agar Gel; D005260:Female; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D019254:Genes, bcl-2 / Q000187:drug effects / Q000235:genetics; D016259:Genes, myc / Q000187:drug effects / Q000235:genetics; D016158:Genes, p53 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011374:Progesterone / Q000008:administration & dosage / Q000627:therapeutic use*; D011419:Propidium; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D013936:Thymidine; D014316:Tritium; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects*
D018931:Antineoplastic Agents, Hormonal; D004396:Coloring Agents; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D014316:Tritium; D011419:Propidium; D011374:Progesterone; D013936:Thymidine