ER stress as a trigger of UPR and ER-phagy in cancer growth and spread

Abstract

Tumors can survive environmental and metabolic stress by triggering homeostatic responses that re-establish the pre-stress status and permit them to grow and thrive. The endoplasmic reticulum (ER) is the organelle where proteins undergo post-translational modifications and are folded and exported to the secretory pathway. Its environment and activity are therefore fundamental for proteostasis, i.e., the plethora of mechanisms controlling protein formation, folding, degradation, and secretion, needed to assure protein balance and cellular health. In different tumor-related conditions, such as after the activation of oncogenes or under hypoxia and nutrient deprivation, the ER experiences stress, triggered by a high load of proteins to be folded compared to the limited folding capacity of the organelle. As a consequence, three ER membrane sensors and the related unfolded protein response (UPR) are activated. The UPR comprises a complex interconnection between signal transduction pathways that promote a homeostatic response that acts by increasing the amount of protein chaperones and of proteins involved in ER-associated protein degradation (ERAD) on one hand and attenuating protein translation on the other. ER-phagy, literally “eating” the ER, is part of another homeostatic response consisting of the clearance of non-functional ER portions including misfolded proteins. This response is also activated by a set of dedicated ER-phagy receptors after ER stimuli, which overlap the stimuli generating ER stress. Thus, the UPR and ER-phagy are two closely related homeostatic mechanisms that cooperate in re-establishing ER homeostasis. However, while the role of the UPR in favoring cancer growth and thriving by promoting angiogenesis, metastasis, chemotherapy resistance, and epithelial-to-mesenchymal transition is consolidated, that of ER-phagy is still in its infancy. This essay provides an overview of emerging concepts on ER stress, the UPR, and ER-phagy and their crosstalk in tumorigenesis. We also critically review new findings on their pharmacological targeting in cancer.

Unraveling the unfolded protein response signature: implications for tumor immune microenvironment heterogeneity and clinical prognosis in stomach cancer

“…The initiation of the UPR in tumor cells, especially when subjected to high levels of endoplasmic reticulum (ER) stress, plays an important survival strategy [23]. When these stress response mechanisms fail to fully correct the protein accumulation problem, the UPR further promotes tumor cells to initiate the process of autophagy, an intracellular recycling mechanism for degrading and recycling defective cellular components, including damaged organelles and protein aggregates [24][25][26]. This process not only helps to maintain the stability of the intracellular environment, but also reduces the risk of cell death due to accumulated damage.…”

Autophagy of the ER: the secretome finds the lysosome

“…Several studies have demonstrated that specific ER‐phagy receptors promote cancer cell survival and migration for certain cancers [104]. This has been most clearly documented with Sec62, CCPG1, and FAM134B.…”

“…Cancer has long been linked to increased ER stress, caused by both intrinsic and extrinsic factors. The uncontrolled proliferation of cancer cells drives increased protein translation and therefore more ER stress; this stress is exacerbated by a tumor microenvironment low in oxygen and nutrients and high in certain fatty acids and other metabolites [104]. This strong link between cancer and ER stress begs the question: what role do the major ER protein quality pathways—including the unfolded protein response (UPR), ER‐associated degradation (ERAD) and ER‐phagy—play in tumorigenesis and metastasis?…”

“…This strong link between cancer and ER stress begs the question: what role do the major ER protein quality pathways-including the unfolded protein response (UPR), ER-associated degradation (ERAD) and ERphagy-play in tumorigenesis and metastasis? Multiple studies have shown that UPR sensors are important in promoting cancer growth, particularly in angiogenesis (formation of blood vessels supplying the tumor) and metastasis [104,105]. However, the role of ER-phagy in cancer remains more mysterious, with researchers disputing whether it plays a tumor-promoting or tumor-suppressing role.…”

LncRNAs and CircRNAs in Endoplasmic Reticulum Stress: A Promising Target for Cardiovascular Disease?

“…Alteration of ER protein folding capacity may cause an increased proportion of unfolded and misfolded proteins in ER lumen which triggers loss of ER homeostasis and proteostasis and generates a detrimental cellular environment [ 6 , 7 , 8 ]. Several molecular and biophysical mechanisms are triggered to reverse and restore ER homeostasis such as (1) ER-associated degradation (ERAD), which triggers the misfolded protein degradation from ER lumen; (2) Unfolded protein response (UPR) involving the restoration of ER proteostasis by activation of three transduction signalling –IRE1, ATF6 and PERK branch-; and (3) Reticulophagy, the process of ER remodelling by autophagy of membranes and associated proteins (see reviews [ 9 , 10 , 11 , 12 , 13 , 14 ]). Pathophysiological factors occurring in cardiovascular diseases (CVDs) such as metabolic derangement, hypoxia, hypertrophy or inflammation require an increased protein expression, thus enhancing the disruption of the cellular proteostasis [ 15 , 16 , 17 , 18 , 19 , 20 , 21 ].…”