Endoplasmic Reticulum Stress Signaling in Cancer Cells

Abstract

To survive, cancer cells must resist numerous internal and environmental insults associated with neoplasia that jeopardize proteostasis within the endoplasmic reticulum (ER). Solid and hematopoietic tumors often experience genomic instability, oncogene activation, increased protein secretion demands, and somatic mutations in proteins handled by the secretory pathway that impede their folding. Invasion or metastasis into foreign environments can expose tumor cells to hypoxia, oxidative stress, lack of growth signals, inadequate amino acid supplies, glucose deprivation, and lactic acidosis, all of which pose challenges for protein processing in the ER. Together, these conditions can promote the buildup of misfolded proteins in the ER to cause ER stress, which then activates the unfolded protein response (UPR). An intracellular signaling network largely initiated by three ER transmembrane proteins, the UPR constantly surveils protein folding conditions within the ER lumen and when necessary initiates counteractive measures to maintain ER homeostasis. Under mild or moderate levels of ER stress, the homeostatic UPR sets in motion transcriptional and translational changes that promote cell adaption and survival. However, if these processes are unsuccessful at resolving ER stress, a terminal UPR program dominates and actively signals cell suicide. This article summarizes the mounting evidence that cancer cells are predisposed to ER stress and vulnerable to targeted interventions against ongoing UPR signaling.

Figure 1

Role of the unfolded protein response (UPR) in cancer. Cancer cells frequently encounter extrinsic stresses that challenge protein folding in the endoplasmic reticulum (ER), including hypoxia, nutrient deprivation, and growth factor withdrawal. Intrinsic stresses, such as oncogene activation, proteasome dysfunction, increased glycolysis, and increased protein secretion, can lead to additional demands on the secretory pathway. Furthermore, genomic instability and somatic mutations that cripple protein folding can lead to ER stress. On detecting an accumulation of ER misfolded proteins, the UPR is initiated by three transmembrane ER proteins: inositol-requiring enzyme 1α (IRE1α; alias endoplasmic reticulum to nucleus signaling), PRK-like ER kinase (PERK; alias eukaryotic translation initiation factor 2 α kinase 3), and activating transcription factor 6α (ATF6α; see text for signaling details). The combined outputs of the UPR can regulate tumor growth at many levels, including cell survival, autophagy, angiogenesis, glycolysis, migration, metastases, and chemoresistance. Modified from Oakes with permission from APS Publications. BiP, binding Ig protein; eIF2α, eukaryotic translation initiation factor 2α; ERAD, ER-associated degradation; Redox, oxidation-reduction; RIDD, regulated IRE1α-dependent decay; RTCB, RNA 2′,3′-cyclic phosphate and 5′-OH ligase; S1P, site-1 protease; S2P, site-2 protease; XBP1, X-box binding protein 1-unspliced; XBP-1s, spliced X-box binding protein 1.

Figure 2

Normal and malignant professional secretory cells are critically dependent on the unfolded protein response (UPR). Plasma cells and pancreatic neuroendocrine cells, two cell types with a high secretory burden, require the UPR for their development and/or function. However, elevated UPR signaling is commonly seen in neoplasms derived from these cells (eg, myeloma and pancreatic neuroendocrine tumors) and appears critical for their growth and survival.