Endoplasmic reticulum proteostasis: a key checkpoint in cancer

Abstract

The unfolded protein response (UPR) is an intracellular signaling network largely controlled by three endoplasmic reticulum (ER) transmembrane proteins, inositol-requiring enzyme 1α, PRK-like ER kinase, and activating transcription factor 6, that monitor the protein-folding status of the ER and initiate corrective measures to maintain ER homeostasis. Hypoxia, nutrient deprivation, proteasome dysfunction, sustained demands on the secretory pathway or somatic mutations in its client proteins, conditions often encountered by cancer cells, can lead to the accumulation of misfolded proteins in the ER and cause "ER stress." Under remediable levels of ER stress, the homeostatic UPR outputs activate transcriptional and translational changes that promote cellular adaptation. However, if the ER stress is irreversible despite these measures, a terminal UPR program supersedes that actively signals cell destruction. In addition to its prosurvival and prodeath outputs, the UPR is now recognized to play a major role in the differentiation and activation of specific immune cells, as well as proinflammatory cytokine production in many cell types. Given the numerous intrinsic and extrinsic factors that threaten the fidelity of the secretory pathway in cancer cells, it is not surprising that ER stress is documented in many solid and hematopoietic malignancies, but whether ongoing UPR signaling is beneficial or detrimental to tumor growth remains hotly debated. Here I review recent evidence that cancer cells are prone to loss of proteostasis within the ER, and hence may be susceptible to targeted interventions that either reduce homeostatic UPR outputs or alternatively trigger the terminal UPR.

Keywords: ATF6; IRE1α; PERK; cancer; endoplasmic reticulum stress; protein misfolding; unfolded protein response.

Fig. 1.

Role of the unfolded protein response (UPR) in cancer. Tumors frequently encounter extrinsic stresses that compromise protein folding in the endoplasmic reticulum (ER), including hypoxia, glucose deprivation, lactic acidosis, oxidative stress, and inadequate amino acid supplies. Moreover, intrinsic stresses, such as oncogene activation, changes in chromosomal number, and increased glycolysis, can all lead to an upregulation in protein translation and additional demands on the secretory pathway. Furthermore, genomic instability and somatic mutations in client proteins of the secretory pathway can cripple their folding and lead to ER stress. In response to an accumulation of ER misfolded proteins, the UPR is initiated by three transmembrane ER proteins: inositol-requiring enzyme 1α (IRE1α; also known as ERN1), PRK-like ER kinase (PERK; also known as EIF2AK3), and activating transcription factor (ATF) 6α. At low levels of ER stress, the bifunctional IRE1α kinase/RNase dimerizes/tetramerizes to cleave a nonconventional intron from XBP1 mRNA, which upon religation encodes the XBP1s transcription that upregulates ER protein-folding and quality control components to promote adaptation. However, if hyperactivated by sustained ER stress, IRE1α oligomerizes, and its relaxed RNase activity endonucleolytically degrades many mRNAs, a process called regulated IRE1α-dependent decay (RIDD), at the ER membrane to cause cell death. PERK signaling downregulates Cap-dependent protein translation through phosphorylation of eIF2α, while upregulating the expression of the ATF4. In the presence of misfolded proteins, ATF6α translocates to the Golgi and is cleaved by the site 1 and site 2 proteases to release the p50 ATF6(N) transcription factor into the cytoplasm before migrating to the nucleus. Together with XBP1s, ATF6(N) increases transcription of targets that expand ER size and increase its protein-folding capacity, as well as that of the ER-associated degradation (ERAD) pathway. The combined outputs of the UPR can influence tumor growth at many levels, including cell survival, angiogenesis, inflammation, antigen presentation, invasion, and metastasis. [Adapted by permission from Macmillan Publishers Ltd: Nature Immunology (Ref. , Fig. 1), copyright 2014.]