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Abstract
The unfolded protein response (UPR) is a cascade of intracellular stress signaling events in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER). Cancer cells are often exposed to hypoxia, nutrient starvation, oxidative stress and other metabolic dysregulation that cause ER stress and activation of the UPR. Depending on the duration and degree of ER stress, the UPR can provide either survival signals by activating adaptive and antiapoptotic pathways, or death signals by inducing cell death programs. Sustained induction or repression of UPR pharmacologically may thus have beneficial and therapeutic effects against cancer. In this review, we discuss the basic mechanisms of UPR and highlight the importance of UPR in cancer biology. We also update the UPR-targeted cancer therapeutics currently in clinical trials.
Highlights
The unfolded protein response (UPR) is a cascade of intracellular stress signaling events in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER)
UPR has two primary functions: 1) to initially restore normal function of the cell by halting protein translation and activating the signaling pathways that lead to increased production of molecular chaperones involved in protein folding [9,10]; 2) to initiate apoptotic pathways to remove the stressed cells when the initial objectives are not achieved within a certain time lapse or the disruption is prolonged [11,12]
ER-associated Protein Degradation (ERAD) is essential for maintaining ER homeostasis, and the disruption of ERAD is closely associated with ER stress-induced apoptosis [14]
Summary
Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. 4. Ron D, Walter P: Signal integration in the endoplasmic reticulum unfolded protein response. 7. Wang G, Yang ZQ, Zhang K: Endoplasmic reticulum stress response in cancer: molecular mechanism and therapeutic potential. Haga N, Saito S, Tsukumo Y, Sakurai J, Furuno A, Tsuruo T, Tomida A: Mitochondria regulate the unfolded protein response leading to cancer cell survival under glucose deprivation conditions.
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