Endoplasmic reticulum stress induced autophagy in cancer and its potential interactions with apoptosis and ferroptosis.

The endoplasmic reticulum (ER) is a dynamic organelle that is a site of the synthesis of proteins and lipids, contributing to the regulation of proteostasis, lipid metabolism, redox balance, and calcium storage/-dependent signaling events. The disruption of ER homeostasis due to the accumulation of misfolded proteins in the ER causes ER stress which activates the unfolded protein response (UPR) system through the activation of IRE1, PERK, and ATF6. Activation of UPR is observed in various cancers and therefore, its association with process of carcinogenesis has been of importance. Tumor cells effectively utilize the UPR system to overcome ER stress. Moreover, ER stress and autophagy are the stress response mechanisms operating together to maintain cellular homeostasis. In human cancers, ER stress-driven autophagy can function as either pro-survival or pro-death in a context-dependent manner. ER stress-mediated autophagy can have crosstalk with other types of cell death pathways including apoptosis and ferroptosis. In this connection, the present review has evaluated the role of ER stress in the regulation of autophagy-mediated tumorigenesis and its interactions with other cell death mechanisms such as apoptosis and ferroptosis. We have also comprehensively discussed the effect of ER stress-mediated autophagy on cancer progression and chemotherapeutic resistance.