In the current study, we aimed to investigate the role of the long isoform of cellular Fas−associated death domain−like interleukin−1beta−converting enzyme (FLICE)−like inhibitory protein (c−FLIP(L)) in ovarian cancer (OC) development by using RNA interference (RNAi) in vitro and in vivo.

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.

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.

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. Copyright © 2010 Elsevier Inc. All rights reserved.

PMID: 20227749 [PubMed − as supplied by publisher] Source: National Library of Medicine.