Abstract
The endoplasmic reticulum (ER) is an interconnected organelle that is responsible for the biosynthesis, folding, maturation, stabilization, and trafficking of transmembrane and secretory proteins. Therefore, cells evolve protein quality-control equipment of the ER to ensure protein homeostasis, also termed proteostasis. However, disruption in the folding capacity of the ER caused by a large variety of pathophysiological insults leads to the accumulation of unfolded or misfolded proteins in this organelle, known as ER stress. Upon ER stress, unfolded protein response (UPR) of the ER is activated, integrates ER stress signals, and transduces the integrated signals to relive ER stress, thereby leading to the re-establishment of proteostasis. Intriguingly, severe and persistent ER stress and the subsequently sustained unfolded protein response (UPR) are closely associated with tumor development, angiogenesis, aggressiveness, immunosuppression, and therapeutic response of cancer. Additionally, the UPR interconnects various processes in and around the tumor microenvironment. Therefore, it has begun to be delineated that pharmacologically and genetically manipulating strategies directed to target the UPR of the ER might exhibit positive clinical outcome in cancer. In the present review, we summarize recent advances in our understanding of the UPR of the ER and the UPR of the ER–mitochondria interconnection. We also highlight new insights into how the UPR of the ER in response to pathophysiological perturbations is implicated in the pathogenesis of cancer. We provide the concept to target the UPR of the ER, eventually discussing the potential of therapeutic interventions for targeting the UPR of the ER for cancer treatment.
Highlights
The endoplasmic reticulum (ER) is a specialized organelle composed of flattened discs and elongated tubules
In the course of tumor development, tumor cells are continuously exposed to a variety of extrinsic and intrinsic perturbations, including an increase in protein synthesis and secretion, deregulated protein degradation, genomic instability, changes in the activation status of tumor suppressors and oncogenes, nutrient deprivation, hypoxia, and acidosis, all of which induce ER stress and subsequently activate the unfolded protein response (UPR). [107,108,109]
The UPR was classically demonstrated to be restricted to the maintenance of proteostasis in specialized secretory cells such as pancreatic β cells, plasma B cells, and salivary glands with the characteristics of accelerated protein synthesis and secretion and continuous generation of ER stress
Summary
The endoplasmic reticulum (ER) is a specialized organelle composed of flattened discs and elongated tubules. Upon ER stress, the dissociation of ATF6 from BiP results in its translocation to the Golgi apparatus, in which ATF6 is cleaved by the Golgi enzymes site 1 protease (S1P) and S2P This processing of ATF6 produces a cleaved cytosolic p50 fragment and as an active transcription factor, the cytosolic p50 fragment upregulates the expression of XBP1 and the genes implicated in protein folding and ERAD processes, thereby leading to the improvement of the folding capacity of the ER, the elimination of the unfolded or misfolded proteins, and the subsequent restoration of proteostasis [35,36]. Cytosolic p50 fragment of ATF6 is responsible for ER expansion as well as lipid biogenesis [37,38]
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