Caspase-3 cleaves XIAP in a positive feedback loop to sensitize melanoma cells to TRAIL-induced apoptosis

摘要: Successful treatment of melanoma is still challenging, because metastasis remain chemoresistant and radioresistant. Accordingly, combinational treatments involving death ligands are mandatory. In a recent study from our lab, the majority out 18 cell lines remained resistant against with ligand TRAIL (tumor necrosis factor related apoptosis inducing ligand). Resistance was shown to be mainly due incomplete processing caspase-3 into catalytically inactive p21 by binding anti-apoptotic protein X-linked inhibitor (XIAP). Co-irradiation sub-lethal ultraviolet (UV) B caused depletion XIAP resulting in synergistic sensitization all but two TRAIL. We show here essentially require initial caspase-mediated cleavage, which promotes proteasomal degradation XIAP. Utilizing specific caspase inhibitors small interfering RNA-mediated knockdown, we further identified responsible for performing cleavage after UVB treatment. Additional evidence suggests an accelerated mitochondrial outer membrane permeabilization response co-treatment UVB, directs release antagonizing factors including Smac. Distraction consequently liberates autocatalytically process active p17. Activated cleaves enhances its activation positive regulatory feedback loop. The molecular mechanism discovered appears have broader implications, also accompany cisplatin-induced cells