Cell intrinsic and extrinsic activators of the unfolded protein response in cancer: Mechanisms and targets for therapy

Abstract

A variety of cell intrinsic or extrinsic stresses evoke perturbations in the folding environment of the endoplasmic reticulum (ER), collectively known as ER stress. Adaptation to stress and re-establishment of ER homeostasis is achieved by activation of an integrated signal transduction pathway called the unfolded protein response (UPR). Both ER stress and UPR activation have been implicated in a variety of human cancers. Although at early stages or physiological conditions of ER stress, the UPR generally promotes survival, when the stress becomes more stringent or prolonged, its role can switch to a pro-cell death one. Here, we discuss historical and recent evidence supporting an involvement of the UPR in malignancy, describe the main mechanisms by which tumor cells overcome ER stress to promote their survival, tumor progression and metastasis and discuss the current state of efforts to develop therapeutic approaches of targeting the UPR.

Keywords: Cancer; ER stress; Therapeutic approaches; Tumorigenesis; UPR.

Figure 1

Cell extrinsic stresses such as hypoxia, nutrient deprivation and acidosis as well as cell intrinsic stresses that result from oncogene activation and loss of tumor suppressors lead to accumulation of unfolded/misfolded proteins in the ER creating an imbalance between nascent polypeptides and chaperones. Upon ER stress, GRP78 (BiP) is titrated away from ER resident transmembrane proteins to help fold nascent polypeptides and misfolded proteins. Activation of PERK, IRE1 and ATF6 is often seen in tumors and found to be important in regulating processes such as transformation, autophagy, ER folding capacity, angiogenesis, metastasis and senescence, thus promoting tumor initiation and progression. However during chronic or severe ER stress that cannot be mitigated, the UPR can also elicit apoptosis which promotes tumor regression. Thus, the UPR can be a double-edged sword during tumorigenesis.