Bcl-2 decreases cell proliferation and promotes accumulation of cells in S phase without affecting the rate of apoptosis in human ovarian carcinoma cells.
OBJECTIVE
The Bcl-2 protein is an important regulator of the apoptotic cascade and promotes cell survival. Bcl-2 can also delay entry into the cell cycle from quiescence. In the present study, we used two isogenic human ovarian carcinoma cell lines, which expressed differential levels of Bcl-2 proteins, to demonstrate that Bcl-2 may regulate the growth rates of adenocarcinoma cells.


METHODS
The growth rates of two isogenic ovarian cancer cell lines were determined by XTT assays and flow cytometry combined with PI staining. Bcl-2-overexpressing SKOV3 cells were modified to express a doxycycline-inducible anti-Bcl-2 single-chain antibody and the effects of Bcl-2 protein inhibition on cell proliferation and apoptosis were assessed.


RESULTS
We demonstrate that Bcl-2 promotes the accumulation of proliferating carcinoma cells in S phase. The Bcl-2-overexpressing SKOV3 cell line proliferates markedly faster and shows delayed progression to G2M phase compared to its low Bcl-2-expressing counterpart SKOV3.ip1 cell line. Single-chain antibody-mediated inhibition of Bcl-2 in SKOV3 cells was associated with increased growth rates and more rapid cell cycle progression. Treatment with cisplatin resulted in more cells accumulating in S phase in Bcl-2-overexpressing SKOV3 cells, while the inhibition of Bcl-2 abolished delayed entry into G2M phase without affecting cisplatin-induced apoptosis.


CONCLUSIONS
Our results suggest that, in ovarian cancer cells, Bcl-2 delays cell cycle progression by promoting accumulation of cells in S phase without affecting the rate of apoptosis. Thus, in addition to its known role at the G0/G1 checkpoint, we demonstrate for the first time that Bcl-2 also regulates the S phase.
Bélanger
Sylvie
S
Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbooke, Canada J1H 5N1.
Côté
Marceline
M
Lane
Denis
D
L'Espérance
Sylvain
S
Rancourt
Claudine
C
Piché
Alain
A
D017209:Apoptosis / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D016195:G2 Phase / Q000502:physiology; D006801:Humans; D007128:Immunoglobulin Fragments / Q000494:pharmacology; D007135:Immunoglobulin Variable Region / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D016196:S Phase / Q000502:physiology*
D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D019253:Proto-Oncogene Proteins c-bcl-2