Cancer and ER stress: Mutual crosstalk between autophagy, oxidative stress and inflammatory response

The endoplasmic reticulum (ER) acts as a moving organelle with many important cellular functions. As the ER lacks sufficient nutrients under pathological conditions leading to uncontrolled protein synthesis, aggregation of unfolded/misfolded proteins in the ER lumen causes the unfolded protein response (UPR) to be activated. Chronic ER stress produces endogenous or exogenous damage to cells and activates UPR, which leads to impaired intracellular calcium and redox homeostasis. The UPR is capable of recognizing the accumulation of unfolded proteins in the ER. The protein response enhances the ability of the ER to fold proteins and causes apoptosis when the function of the ER fails to return to normal. In different malignancies, ER stress can effectively induce the occurrence of autophagy in cells because malignant tumor cells need to re-use their organelles to maintain growth. Autophagy simultaneously counteracts ER stress-induced ER expansion and has the effect of enhancing cell viability and non-apoptotic death. Oxidative stress also affects mitochondrial function of important proteins through protein overload. Mitochondrial reactive oxygen species (ROS) are produced by calcium-enhanced ER release. The accumulation of toxic substances in ER and mitochondria in mitochondria destroys basic organelle function. It is known that sustained ER stress can also trigger an inflammatory response through the UPR pathway. Inflammatory response is thought to be associated with tumor development. This review discusses the emerging links between UPR responses and autophagy, oxidative stress, and inflammatory response signals in ER stress, as well as the potential development of targeting this multifaceted signaling pathway in various cancers.