Kunming University of Science and Technology, China
Posters & Accepted Abstracts: J Cancer Sci Ther
The discovery of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its death receptors DR4/5 changed the horizon of cancer research because TRAIL specifically kills cancer cells. However, the validity of TRAIL-based cancer therapies has yet to be established, as most cancer cells are TRAIL-resistant. In our research, we demonstrate that TRAIL-resistance of many cancer cell lines can be overcome after siRNA- or rocaglamide-mediated downregulation of cellular Fas-associated death domainlike interleulin-1 ├?┬▓ converting enzyme inhibitory protein (c-FLIP) expression and simultaneous inhibition of inhibitors of apoptosis protein (IAP) activity using AT406, a pan-antagonist of IAPs. Combined triple actions of the TRAIL, the IAPs inhibitor, AT406, and the c-FLIP expression inhibitor, rocaglamide (ART), markedly improve TRAIL-induced apoptotic effects in most solid cancer cell lines through the activation of an extrinsic apoptosis pathway. Furthermore, this ART combination has no harm to normal cells. Among the 18 TRAIL-resistant cancer cell lines used, 15 cell lines become sensitive or highly sensitive to ART, and two out of three glioma cell lines exhibit high resistance to ART treatment due to very low levels of procaspase-8. However, c-FLIP downregulation by c-FLIP-siRNA or rocaglamide was cytotoxic to normal cells. Therefore, it is highly desirable to develop a specific disruptor or antagonist of c-FLIP-FADD interactions to avoid the cytotoxicity caused by changes in the cellular levels of c-FLIP in normal cells. Furthermore, based on the interaction of c-FLIP with FADD, we investigated on the specific antagonist of c-FLIP. We found that one peptide containing six amino acids could bind c-FLIPs (180aa) protein strongly by affinity chromatography. This finding will help us to get the specific antagonist to c-FLIP. Our study provides a rationale for the development of TRAIL-induced apoptosis-based cancer therapies.
Cancer Science & Therapy received 3644 citations as per Google Scholar report