Sensitization of melanoma cells for TRAIL-induced apoptosis by BMS-345541 correlates with altered phosphorylation and activation of Bax

摘要: Resistance to TRAIL (TNF-related apoptosis-inducing ligand)- induced apoptosis limits its therapeutic use. Different strategies of sensitization and a dependency on Bax have been reported, but common principles resistance the way activation remained poorly understood. Applying melanoma model TRAIL-sensitive -resistant cell lines, efficient for TRAIL-induced is demonstrated by kinase inhibitor BMS-345541 (N-(1,8-dimethylimidazo(1,2-a)quinoxalin-4-yl)-1,2-ethanediamine hydrochloride), which targets IκB (inhibitor κB proteins) β (IKKβ). This effect was completely abrogated knockout as well Bcl-2 overexpression, in accordance with dependency. Early loss mitochondrial membrane potential, release cytochrome c Smac (second mitochondria-derived activator caspases) clearly indicated pathways. Of note, alone resulted an early activation, seen conformational changes translocation. The synergistic effects can be explained Bid through TRAIL, inhibits Bcl-2, BMS-345541. critical roles XIAP (X-chromosome-linked protein), were proven overexpression siRNA knockdown, respectively. unraveled establishing new assays activation. These showed reduction inactivating phosphorylation at serine-184, while activating threonine-167 enhanced. Thus, modulation appeared tightly related sensitivity/resistance cells, may considered.