Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer

Abstract

The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER), due to genetic determinants and extrinsic environmental factors, leads to endoplasmic reticulum stress (ER stress). As ER stress ensues, the unfolded protein response (UPR), comprising three signaling pathways-inositol-requiring enzyme 1, protein kinase R-like endoplasmic reticulum kinase, and activating transcription factor 6 promptly activates to enhance the ER's protein-folding capacity and restore ER homeostasis. However, prolonged ER stress levels propels the UPR towards cellular demise and the subsequent inflammatory cascade, contributing to the development of human diseases, including cancer, neurodegenerative disorders, and diabetes. Notably, increased expression of all three UPR signaling pathways has been observed in these pathologies, and reduction in signaling molecule expression correlates with decreased proliferation of disease-associated target cells. Consequently, therapeutic strategies targeting ER stress-related interventions have attracted significant research interest. In this review, we elucidate the critical role of ER stress in cancer, metabolic, and neurodegenerative diseases, offering novel therapeutic approaches for these conditions.

Keywords: Cancer; Endoplasmic reticulum stress; Metabolic; Neurodegenerative diseases; Signaling pathway; Therapeutic strategies.

Fig. 1

Summary of UPR signaling pathway. Under homeostatic conditions, PERK, IRE1, and ATF6 bind to immunoglobulin binding protein (Bip), inhibiting their activity. During ER stress, Bip dissociates, and PERK, IRE1, and ATF6 become activated. PERK dimerises and phosphorylates eIF2α, impeding the assembly of 80 S ribosomes, resulting in the inhibition of protein translation. Additionally, eIF2α induces the translation of activating transcription factor 4 (ATF4) and activates enhancer-binding protein C/EBP homologous protein (CHOP) expression, culminating in the induction of apoptosis. Activated IRE1 dimerises and triggers its endonuclease activity, leading to the degradation of mRNA in the ER and a consequent reduction in protein biosynthesis. Simultaneously, IRE1 cleaves the transcript encoding X box-binding protein 1 (XBP1), inducing endoplasmic reticulum-associated degradation (ERAD) gene expression, accelerating protein folding, and facilitating the degradation of misfolded proteins. ATF6 translocates to the Golgi, where it undergoes cleavage and activation by the S1 and S2 proteases, thereby activating the transcription of UPR target genes. (ER stress, endoplasmic reticulum stress; UPR, unfolded protein response; PERK, protein kinase R-like endoplasmic reticulum kinase; IRE1, inositol-requiring enzyme 1; ATF6, activating transcription factor 6; ATF4, activating transcription factor 4; Bip, immunoglobulin binding protein; eIF2α, eukaryotic initiation factor 2α; CHOP, enhancer-binding protein C/EBP homologous protein; XBP1, X box-binding protein 1; ERAD, endoplasmic reticulum-associated degradation.)

Fig. 2

ER stress and human diseases triggered by misfolded protein aggregates. Environmental conditions, such as genetic mutations, hypoxia, and oxidative stress, disrupt ER homeostasis, leading to protein misfolding and accumulation. This, in turn, induces ER stress and expedites the build-up of disease-associated protein aggregates. The activation of the UPR signaling pathway serves to alleviate ER stress. However, when sustained ER stress surpasses the adaptive response capacity to manage protein misfolding, it can culminate in cell death, inflammation, and the proliferation of cancer cells, consequently contributing to disease progression. (ER stress, endoplasmic reticulum stress; UPR, unfolded protein response; PERK, protein kinase R-like endoplasmic reticulum kinase; IRE1, inositol-requiring enzyme 1; ATF6, activating transcription factor 6; Bip, immunoglobulin binding protein; eIF2α, eukaryotic initiation factor 2α.)