The role of c-FLIP L in ovarian cancer: Chaperoning tumor cells from immunosurveillance and increasing their invasive potential

Abstract

Objective In the current study, we aimed to investigate the role of the long isoform of cellular Fas-associated death domain-like interleukin-1β-converting enzyme (FLICE)-like inhibitory protein (c-FLIP L) in ovarian cancer (OC) development by using RNA interference (RNAi) in vitro and in vivo. Methods TRAIL-resistant human OC cell lines were genetically manipulated by RNAi-mediated suppression of c-FLIP L. Subsequently, the genetic alteration that was introduced into the various OC cell lines was characterized in vitro and in vivo. Results We previously showed that about 40% of OC patients express high levels of c-FLIP L, and that natural killer (NK) cells mediated immunosurveillance in OC. In the present study, we observed that the knockdown of c-FLIP L in human OC cell lines not only enhanced their sensitivity to TRAIL-mediated apoptosis, but also inhibited their migratory phenotype in a TRAIL-dependent manner in vitro. Shutdown of c-FLIP L in OC cells significantly decreased tumor development by induction of apoptosis and reduction of proliferation in vivo. Importantly, the knockdown of c-FLIP L particularly inhibited the invasion of OC cells into the peritoneal cavity, which might be due to high expression of TRAIL by NK cells and NK-cell mediated immunosurveillance. Conclusion These data demonstrate that c-FLIP L exhibits multiple functions in OC cells: first by concomitantly evading the natural immunity mediated by TRAIL-induced cell death, and second by augmenting cell motility and invasion in vivo. Our findings indicate that c-FLIP L regulates sensitivity of OC to TRAIL-mediated apoptosis and offers possible therapeutical implications for OC in the future.