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-X-L on the growth and survival of human ovarian carcinoma cells. Methods. In this study, we enforced down-regulation of Bcl-X-L by RNA interference in ovarian carcinoma cell lines CaOV3, SKOV3ipl and OVCAR3 cell lines expressing various levels of Bcl-X-L. We also established stable transfectants of OVCAR3 cells overexpressing Bcl-X-L, We recently showed that Bcl-2 regulates cell cycle progression in ovarian cancer cells. Thus, the effect of Bcl-X-L modulation on the rate of cell growth was determined by XTT assay. To evaluate the role of Bcl-X-L 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-X-L 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-X-L protein significantly affected the growth rates of CaOV3 whereas it had only minimal effect on the other two cell lines. Down-regulation of Bcl-X-L enhanced the sensitivity of CaOV3, OVCAR3 and SKOV3ipl 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-X-L 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-X-L Will likely yield variable responses. (c) 2005 Elsevier Inc. All rights reserved.