Linking ER Stress to Autophagy: Potential Implications for Cancer Therapy
Mechanisms connecting ER stress and autophagy. Different ER stresses lead to autophagy activation. release from the ER can stimulate different kinases that regulate autophagy. CaCMKK phosphorylates and activates AMPK which leads to mTORC1 inhibition; DAPK phosphorylates Beclin-1 promoting its dissociation from Bcl-2; PKCθ activation may also promote autophagy independently of mTORC1. Inositol 1,4,5-trisphosphate receptor (IP3R) interacts with Beclin-1. Pharmacological inhibition of IP3R may lead to autophagy in a -independent manner by stimulating its dissociation from Beclin-1. The IRE1 arm of ER stress leads to JNK activation and increased phosphorylation of Bcl-2 which promotes its dissociation from Beclin-1. Increased phosphorylation of eIF2 in response to different ER stress stimuli can lead to autophagy through ATF4-dependent increased expression of Atg12. Alternatively, ATF4 and the stress-regulated protein p8 promote the up-regulation of the pseudokinase TRB3 which leads to inhibition of the Akt/mTORC1 axis to stimulate autophagy.