Endoplasmic reticulum stress-mediated autophagy in cancer and its interaction with apoptosis and ferroptosis

Abstract

The endoplasmic reticulum (ER) is a dynamic organelle that is a site of the synthesis of proteins and lipids and contributes 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 the tumor cells effectively utilize the UPR system to overcome ER stress. Also, ER stress and autophagy are the stress response mechanisms that operate together to maintain cellular homeostasis. In cancers, ER stress-mediated 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 article, we have reviewed 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.