The alteration of mitochondrial function is associated with the induction of endoplasmic reticulum stress autophagy and apoptosis by Sorafenib in liver cancer cells

Sorafenib is the accepted molecular therapy for advanced hepatocarcinoma. Sorafenib reduced mitochondrial oxygen consumption, polarization and superoxide anion production in HepG2. These effects paralleled the induction of endoplasmic reticulum stress which was associated with Thr183JNK/JNK, Thr172AMPα, Thr308Akt/Akt and Thr32Foxo3a/Foxo3a increased ratios, as well as the reduction of Ser2481mTOR/mTOR and polysome profiling. This pattern was related to increased autophagy, and downregulation of Mcl-1 and Bcl-2 expression. The reduction of Thr308P-AKt/AKt and Ser473P-AKt/AKt ratios was associated with the progressive increase of CHOP and Bim expression. si-RNA and immunoprecipitation assays showed that Beclin-1 sequestration by Bim shifted autophagy to caspase-3-related apoptosis. Sorafenib appeared to be inactive in primary non-tumoral human hepatocytes. Sorafenib induced autophagy and apoptosis in xenograft mice model. In conclusion, the induction of mitochondrial dysfunction was associated with endoplasmic reticulum stress which was the driving mechanism involved in the sequential induction of autophagy and Bim-related apoptosis. Bim expression might also be related to the tight balance between AKt- and AMPK-related signaling in Foxo3a-dependent Bim upregulation.