Bcl-XL is functionally non-equivalent for the regulation of growth and survival in human ovarian cancer cells

Objective.To investigate the role of Bcl-XL on the growth and survival of human ovarian carcinoma cells.Methods.In this study, we enforced down-regulation of Bcl-XL by RNA interference in ovarian carcinoma cell lines CaOV3, SKOV3ip1 and OVCAR3 cell lines expressing various levels of Bcl-XL. We also established stable transfectants of OVCAR3 cells overexpressing Bcl-XL. We recently showed that Bcl-2 regulates cell cycle progression in ovarian cancer cells. Thus, the effect of Bcl-XL modulation on the rate of cell growth was determined by XTT assay. To evaluate the role of Bcl-XL in drug-induced apoptosis, cisplatin- and paclitaxel-induced apoptosis were determined in vitro for each of the three cell lines. Ovarian tumor cells must acquire the ability to survive in non-adherent conditions to grow in ascetic fluids. To mimic loss of anchorage and investigate the role of Bcl-XL in this process, cells were cultured on Hydrogel-coated plates and nuclear fragmentation, caspase-3 activation and nuclear propidium iodide staining were used to determine apoptosis.Results.We show that enforced down-regulation of Bcl-XL protein significantly affected the growth rates of CaOV3 whereas it had only minimal effect on the other two cell lines. Down-regulation of Bcl-XL enhanced the sensitivity of CaOV3, OVCAR3 and SKOV3ip1 to cisplatin and paclitaxel. The susceptibility to apoptosis induced by loss of anchorage was also increased but in a cell line-dependent manner. Overexpression of Bcl-XL slowed the growth of OVCAR3 cells and conferred resistance to drug-induced apoptosis and apoptosis induced by loss of anchorage.Conclusion.Altogether, these findings demonstrate that modulation of Bcl-XL provokes changes in ovarian cancer cell growth and survival that are cell line-specific. Consequently, therapeutic strategy for treatment of ovarian cancer that target Bcl-XL will likely yield variable responses.