Fig. 1

Role of the unfolded protein response (UPR) in cancer. Cancer cells frequently encounter intrinsic and extrinsic stresses that disturb protein folding in the endoplasmic reticulum (ER), including oncogene activation, hypoxia, nutrient deprivation, drug-induced toxicity, and low pH, which trigger ER stress to reestablish intracellular homeostasis. Upon detecting an accumulation of ER unfolded and misfolded proteins, the UPR is initiated by three transmembrane ER proteins: inositol-requiring enzyme 1(IRE1), protein kinase RNA-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Once ER stress occurs, Bip dissociates from these three ER membrane enzymes, resulting in their activation and initiating the relevant downstream signaling pathway. Activation of the UPR can transcriptionally regulate tumor characteristics