The interaction between Hsp90-mediated unfolded protein response and autophagy contributes to As3+/ Se4+ combination-induced apoptosis of acute promyelocytic leukemia cells

The interaction between the unfolded protein response (UPR) and autophagy plays either pro-survival or pro-apoptotic roles in the treatment of acute promyelocytic leukemia (APL). Our previous study has shown that the combination therapy of arsenite (As3+) and selenite (Se4+) induces apoptosis in APL NB4 cells, although the mechanisms are not clear. Here, we demonstrate that the interaction between heat shock protein 90 (Hsp90)-mediated UPR and autophagy is the core module for As3+/Se4+ combination-induced apoptosis. Hsp90 overexpression and knockdown assays indicate that Hsp90 inhibition by PERK modulates two branches of the UPR, leading to the activation of ATF4 and CHOP, causing the degradation of IRE1α and the dephosphorylation of eIF2α, thereby contributing to switching the cytoprotective UPR into an apoptotic pathway. Assays using pretreatment with inducers and inhibitors of endoplasmic reticulum stress (ERS) and autophagy reveal that autophagy is stimulated by ERS but suppressed by As3+/Se4+ combination via the mTOR signaling pathway. However, inhibition of autophagy decreases GRP78 expression and eIF2α phosphorylation, thereby further promoting ERS-induced apoptosis. Moreover, As3+/Se4+ combination blocks hepatic infiltration in an APL-NCG mouse model of extramedullary infiltration. Taken together, these findings provide novel agents and therapeutic approaches for APL.