Cell type-dependent ROS and mitophagy response leads to apoptosis or necroptosis in XXXX .

@entity1 @entity26 @entity467 @entity10614 @entity8783 @entity70808 @entity10615 @entity521
UNASSIGNED: A limiting factor in the therapeutic outcome of @entity1 with high-risk @entity521 is the intrinsic and acquired resistance to common chemotherapeutic treatments. Here we investigated the molecular mechanisms by which the hemisynthetic cardiac glycoside @entity70808 overcomes this limitation and induces differential cell death modalities in both neuroblastic and stromal @entity521 through stimulation of a cell-type-specific autophagic response eventually leading to apoptosis or necroptosis. In neuroblastic SH-SY5Y cells, we observed a time-dependent production of reactive @entity26 species that affects lysosomal integrity inducing lysosome-associated membrane protein 2 degradation and @entity467 and L activation. Subsequent mitochondrial membrane depolarization and accumulation of mitochondria in phagophores occurred after 8h of @entity70808 treatment. Results were confirmed by mitochondrial mass analysis, electron microscopy and co-localization of mitochondria with GFP-LC3, suggesting the impaired clearance of damaged mitochondria. Thus, a stress-induced defective autophagic flux and the subsequent lack of clearance of damaged mitochondria sensitized SH-SY5Y cells to @entity70808 -induced apoptosis. Inhibition of autophagy with small inhibitory RNAs against @entity10614 , @entity10615 and @entity8783 protected SH-SY5Y cells against the cytotoxic effect of @entity70808 by inhibiting apoptosis. In contrast, autophagy progression towards the catabolic state was observed in stromal SK-N-AS cells: here reactive @entity26 species (ROS) generation remained undetectable preserving intact lysosomes and engulfing damaged mitochondria after @entity70808 treatment. Moreover, autophagy inhibition determined sensitization of SK-N-AS to apoptosis. We identified efficient mitophagy as the key mechanism leading to failure of activation of the apoptotic pathway that increased resistance of SK-N-AS to @entity70808 , triggering rather necroptosis at higher doses. Altogether we characterize here the differential modulation of ROS and mitophagy as a @entity521 resistance with potential relevance for personalized anticancer therapeutic approaches.Oncogene advance online publication, 7 December 2015; doi:10.1038/onc.2015.455.
