Protein Quality Control in the Endoplasmic Reticulum and Cancer

Abstract

The endoplasmic reticulum (ER) is an essential compartment of the biosynthesis, folding, assembly, and trafficking of secretory and transmembrane proteins, and consequently, eukaryotic cells possess specialized machineries to ensure that the ER enables the proteins to acquire adequate folding and maturation for maintaining protein homeostasis, a process which is termed proteostasis. However, a large variety of physiological and pathological perturbations lead to the accumulation of misfolded proteins in the ER, which is referred to as ER stress. To resolve ER stress and restore proteostasis, cells have evolutionary conserved protein quality-control machineries of the ER, consisting of the unfolded protein response (UPR) of the ER, ER-associated degradation (ERAD), and autophagy. Furthermore, protein quality-control machineries of the ER play pivotal roles in the control of differentiation, progression of cell cycle, inflammation, immunity, and aging. Therefore, severe and non-resolvable ER stress is closely associated with tumor development, aggressiveness, and response to therapies for cancer. In this review, we highlight current knowledge in the molecular understanding and physiological relevance of protein quality control of the ER and discuss new insights into how protein quality control of the ER is implicated in the pathogenesis of cancer, which could contribute to therapeutic intervention in cancer.

Synthetic lethality screening identifies FDA-approved drugs that overcome ATP7B-mediated tolerance of tumor cells to cisplatin

“…However, GO analysis revealed that transcriptional response to Tranilast and Amphotericin B shares suppression of several cisplatin resistance pathways including DNA repair (28), antiapoptotic NFKB signaling (25) and protein quality control (27). In addition to these mechanisms, we noted that both drugs reduced expression of autophagy genes.…”

“…Using a synthetic lethality screening we revealed and validated 3 hits, which significantly reduced ATP7B-mediated tolerance to cisplatin in ovarian cancer cells. The drugs acted via blocking ATP7B export from the Golgi and down-regulating large cohorts of genes, which belong to cisplatin-resistance pathways including DNA repair, quality control and autophagy (25)(26)(27)(28). Our findings underscore the effectiveness of unbiased screening approach for drug repurposing studies and pinpoint bio-safe drug candidates to combat ATP7B-mediated resistance of tumors to cisplatin.…”

“…GO analysis of Tranilast-and Amphotericin Btreated cells revealed several statistically significant GO enrichments that exhibited a similar trend in several groups of down-regulated genes ( Figure 5D). These include DNA repair; protein quality control, ubiquitination and folding; macroautophagy and NFKB signaling, which all were reported to promote cisplatin resistance (25)(26)(27)34). Overall, among a total of 19 significant GO biological clusters identified in the down-regulated genes, 4 pathways were found in common between Amphotericin B and Tranilast ( Figure 5D).…”

Endoplasmic Reticulum Associated Degradation (ERAD) Deficiency Promotes Mitochondrial Dysfunction and Transcriptional Rewiring in Human Hepatic Cells

“…Increasing evidence links ER stress to the development of chronic human diseases, such as type 2 diabetes mellitus, NAFLD, neurodegeneration and cancer [1][2][3]. However, the mechanisms whereby ER stress leads to the pathogenesis of various human diseases is incompletely understood.…”

“…The endoplasmic reticulum (ER) serves several critical cellular functions, including Ca2+ storage, lipid synthesis and the folding of protein molecules destined for the secretory pathway. Impaired ER function or ER stress has been implicated in a increasing number of chronic human diseases, including obesity, diabetes, neurodegeneration, non-alcohol fatty liver disease (NAFLD) and cancer [1][2][3]. ER stress is an abnormal homeotic condition characterized by the accumulation of unfolded or misfolded proteins in the ER lumen [4].…”