The Impact of the ER Unfolded Protein Response on Cancer Initiation and Progression: Therapeutic Implications

Cellular stress induced by the accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates an elaborate signalling network termed the unfolded protein response (UPR). This adaptive response is mediated by the transmembrane signal transducers IRE1, PERK, and ATF6 to decide cell fate of recovery or death. In malignant cells, UPR signalling may be required to maintain ER homeostasis and survival in the tumor microenvironment characterized by oxidative stress, hypoxia, lactic acidosis and compromised protein folding. Here we provide an overview of the ER response to cellular stress and how the sustained activation of this network enables malignant cells to develop tumorigenic, metastatic and drug-resistant capacities to thrive under adverse conditions. Understanding the complexity of ER stress responses and how to target the UPR in disease will have significant potential for novel future therapeutics.