Endogenous Bak inhibitors Mcl-1 and Bcl-xL: differential impact on TRAIL resistance in Bax-deficient carcinoma

摘要: Tumor necrosis factor (α)–related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that preferentially kills tumor cells with limited cytotoxicity to nonmalignant cells. However, signaling from death receptors requires amplification via the mitochondrial apoptosis pathway (type II) in majority of Thus, TRAIL-induced cell entirely depends on proapoptotic Bcl-2 family member Bax, which often lost as result epigenetic inactivation or mutations. Consequently, Bax deficiency confers resistance against apoptosis. Despite expression Bak, Bax-deficient are resistant In this study, we show dependency determined by Mcl-1 but not Bcl-xL. Both antiapoptotic proteins keep Bak check. Nevertheless, knockdown Bcl-xL overcame TRAIL, CD95/FasL and (α) receptor ligation cells, enabled TRAIL activate indicating rather than major target for sensitization tumors receptor–induced pathway.