FIGURE 6.

Proteasome inhibition by VLX1570 induces ROS generation and the activation of unfolded protein response under ER stress followed by apoptosis. VLX1570 induces apoptosis mainly through ROS stress signaling and the unfolded protein response pathway under ER stress. Regarding the PERK signaling pathway, VLX1570 increases the amount of phospho‐eIF2α and the expression of the downstream molecules, ATF4 and CHOP, induction of ER stress‐dependent apoptosis. As another pathway, excess accumulation of polyubiquitinated proteins on the mitochondria induces ROS generation, followed by phosphorylation of JNK and p38, leading to caspase‐3‐ and 9‐dependent apoptosis