Oxidative phosphorylation-dependent regulation of XXXX cell apoptosis in response to anticancer agents.

@entity632 @entity1605 @entity2426 @entity5 @entity14377 @entity1311 @entity2857 @entity2879 @entity876 @entity866 @entity164 @entity952 @entity2383
@entity5 cells tend to develop resistance to various types of anticancer agents, whether they adopt similar or distinct mechanisms to evade cell death in response to a broad spectrum of @entity5 therapeutics is not fully defined. Current study concludes that DNA-damaging agents ( @entity2879 and @entity632 ), ER stressor ( @entity2426 ), and histone deacetylase inhibitor (apicidin) target oxidative phosphorylation (OXPHOS) for apoptosis induction, whereas other anticancer agents including @entity866 , @entity1311 , and @entity2857 induce apoptosis in an OXPHOS-independent manner. DNA-damaging agents promoted mitochondrial biogenesis accompanied by increased accumulation of cellular and mitochondrial ROS, mitochondrial protein-folding machinery, and mitochondrial unfolded protein response. Induction of mitochondrial biogenesis occurred in a caspase activation-independent mechanism but was reduced by autophagy inhibition and @entity876 -deficiency. Abrogation of complex-I blocked DNA-damage-induced caspase activation and apoptosis, whereas @entity14377 or a combined deficiency of OXPHOS complexes I, III, IV, and V due to impaired mitochondrial protein synthesis did not modulate caspase activity. Mechanistic analysis revealed that inhibition of caspase activation in response to anticancer agents associates with decreased release of mitochondrial cytochrome c in complex-I-deficient cells compared with @entity164 ( @entity164 ) cells. Gross @entity2383 promoted increased release of apoptosis-inducing factor from mitochondria compared with @entity164 or complex-I-deficient cells, suggesting that cells harboring defective OXPHOS trigger caspase-dependent as well as caspase-independent apoptosis in response to anticancer agents. Interestingly, DNA-damaging agent @entity632 showed strong binding to mitochondria, which was @entity952 but not by @entity1605 . @entity2426 -induced caspase activation was reduced upon @entity2383 whereas a reverse trend was observed with apicidin. Together, these finding provide a new strategy for differential mitochondrial targeting in @entity5 therapy.
