The role of c-FLIP(L) in ovarian cancer: chaperoning tumor cells from immunosurveillance and increasing their invasive potential.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Division of Oncology, Department of Medicine I, Medical University of Vienna, Austria.
Ahmed
A
El-Gazzar
Michael
M
Wittinger
Paul
P
Perco
Mariam
M
Anees
Reinhard
R
Horvat
Wolfgang
W
Mikulits
Thomas W
TW
Grunt
Bernd
B
Mayer
Michael
M
Krainer
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007157:Immunologic Surveillance; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D034741:RNA, Small Interfering / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human