Molecular pathways: the PERKs and pitfalls of targeting the unfolded protein response in cancer

The endoplasmic reticulum (ER) is a highly specialized organelle that provides an oxidizing, profolding environment for protein synthesis and maturation. The ER also hosts a dynamic signaling network that can sense and respond to physiologic changes that affect its environment, thereby influencing overall cell fate. Limitation of nutrients and oxygen have a direct effect on the efficiency of protein folding in the ER, and are classic inducers of the ER resident signaling pathway, the unfolded protein response (UPR). Not only does the UPR regulate ER homeostasis in normal cells experiencing such stress, but strong evidence also suggests that tumor cells can co-opt the cytoprotective aspects of this response to survive the hypoxic, nutrient-restricted conditions of the tumor microenvironment.