IRE1α deficiency promotes tumor cell death and eIF2α degradation through PERK dipendent autophagy

Sensors of endoplasmic reticulum (ER) stress function in a co-ordinated manner. In the present study we investigated the relationship between IRE1 alpha and PERK pathways and survival of ER stressed U937 cells and BC3 cells. To this end, we investigated the effects of a subcytotoxic concentration of Tunicamycin in IRE1 alpha-proficient and in IRE1 alpha-deficient cells, by pharmacological inhibition with 4 mu 8 C or down-regulation by specific siRNA. We show that either type of IRE1 alpha deficiency affects eIF2 alpha expression and causes cell death increase. GSK2606414, a PERK inhibitor, and PERK specific siRNA prevent eIF2 alpha down-regulation and restore cell survival. Degradation of this protein is due to autophagy, as it is prevented by bafilomycin and not by proteasome inhibition. Furthermore, activation of the autophagy flux is PERK dependent. Also the Cathepsin B inhibitor CA074 prevents eIF2 alpha from degradation and reduces cell death. Altogether, these results show that IRE1 alpha deficiency in ER stressed cells leads to an unexpected decrease of eIF2 alpha, an important molecule for protein translation, through PERK dependent autophagy. Thus, IRE1/XBP1 inhibitors may represent a feasible strategy for tumor therapy, while PERK inhibitors may vanish the goal.