The Regulation of the Unfolded Protein Response and Its Roles in Tumorigenesis and Cancer Therapy

Abstract

The unfolded protein response (UPR) of the endoplasmic reticulum (ER) is a highly conserved system by which cells regulate multiple pathways during misfolded protein accumulation. Acute UPR signaling inhibits translation, induces chaperone expression, and activates proteolysis, whereas chronic UPR signaling can lead to apoptosis. Each of the canonical functions of UPR serves as a mechanism that can limit or facilitate tumorigenesis. Tumor cells are able to coopt UPR signaling to facilitate proliferation, transformation, and epithelial-to-mesenchymal transition (EMT) under hypoxia and glucose starvation, potentially causing metastasis. UPR signaling is typically initiated by Glucose-Regulated Protein 78 (GRP78/BiP) binding to unfolded proteins, causing GRP-78 to dissociate from each of the three primary UPR sensors on the ER membrane: protein kinase R-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring protein 1α (IRE1α). Recent studies highlight the complexity of the signaling interactions involved, but also potential clinical opportunities to target unique molecular interfaces. This review discusses the current understanding of UPR pathways, ongoing clinical approaches to manipulate UPR signaling, and future avenues by which cancer therapy may be advanced by utilizing approaches that target the molecules involved in UPR signaling.