Development of Gene Therapy With TRAIL for Prostate Cancer
Annual summary 15 Aug 2001-14 Aug 2003
PITTSBURGH UNIV PA
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Tumor necrosis factor-related apoptosis inducing ligand TRAILApo2L is considered as one of the most promising cancer therapeutic agents due to its ability to selectively kill tumor cells. In this study, we investigated whether low extracellular pH affects TRAIL- induced apoptotic death. When human prostate carcinoma DU145 cells were treated with 200 ngml TRAIL for 4 h, the survival was 10 at pH 6.3-6.6 and 61.3 at pH 7.4. The TRAIL- mediated activation of caspase, cytochrome C release, and PARP cleavage were promoted at low extracellular pH. Western blot analysis shows that the low extracellular pH-enhanced TRAIL cytotoxicity does not involve modulation of the levels of TRAIL receptors DR4, DR5, and DcR2, FLIP, lAP and Bcl-2. Overexpression of Bcl-2 effectively prevented low extracellular pH augmented TRAIL cytotoxicity. Immunoprecipitation followed by western blot analysis shows that low extraceliular pH enhances the association of trunacated Bid with Bax during treatment with TRAIL. Taken together, we propose that TRAIL-mediated cytotoxicity is greatly enhanced in low pH environments by facilitating interaction between Bax and truncated Bid and subsequently promoting the mitochondria-mediated apoptotic signal transduction.
- Medicine and Medical Research