Negative feedback and modern anti‐cancer strategies targeting the ER stress response

Abstract

Endoplasmic reticulum (ER) stress is a cell state in which misfolded or unfolded proteins are aberrantly accumulated in the ER. ER stress induces an evolutionarily conserved adaptive response, named the ER stress response, that deploys a self-regulated machinery to maintain cellular proteostasis. However, compared to its well-established canonical activation mechanism, the negative feedback mechanisms regulating the ER stress response remain unclear and no accepted methods or markers have been established. Several studies have documented that both endogenous and exogenous insults can induce ER stress in cancer. Based on this evidence, small molecule inhibitors targeting ER stress response have been designed to kill cancer cells, with some of them showing excellent curative effects. Here, we review recent advances in our understanding of negative feedback of the ER stress response and compare the markers used to date. We also summarize therapeutic inhibitors targeting ER stress response and highlight the promises and challenges ahead.

Unfolded Protein Response Is Activated by Aurora Kinase A in Esophageal Adenocarcinoma

“…Analysis of TCGA, GEO databases, and human tissue samples demonstrated a robust positive correlation between AURKA and increased UPR/ER stress in EAC. Recent studies indicated that IRE1α, PERK, and ATF6 are essential ER stress sensors, regulating the balance between cell survival and death during ER stress through UPR [33]. Our data not only indicated a remarkable increase in UPR proteins in EAC cells but also showed the critical prosurvival role of IRE1α compared with the other two primary ER stress sensors, PERK and ATF6.…”

“…As we showed the co-overexpression of AURKA and UPR key proteins, our data indicated that AURKA induced IRE1α levels and phosphorylation in EAC cells. IRE1α and its downstream sXBP1 promote cell survival during ER stress in several malignancies [33,46].…”

“…UPR is known to be activated under ER stress in both normal and cancer cells [31,32]. Since few reports are published on the relationship of AURKA and ER stress, we further looked at our esophageal tissue samples and the TCGA database for BIP mRNA, a marker of ER stress [33] AURKA mRNA expression in EAC. Using RT-PCR in 30 normal esophageal samples and 32 EAC tissues, we detected a significant overexpression of both AURKA and BIP mRNA in EAC samples compared with the normal esophagus (NE) (Figure 1B, p < 0.01).…”

“…Western blot results demonstrated that AURKA, p-IRE1α (S724) IRE1α, BIP, XBP1s, p-PERK (T982) PERK, and p-eIF2α(S51) protein expression levels were remarkably higher in Barrett's esophagus and EAC cells compared with normal esophageal tissues (Figure 2A). IRE1α, PERK, and ATF6 are three well-known sensors that activate UPR, controlling the balance between cell survival and apoptosis during ER stress in cancer [33,34]. To test which sensors are vital in EAC cell models, we knocked down these proteins respectively in EAC cell lines using siRNA.…”

PDIA2 Bridges Endoplasmic Reticulum Stress and Metabolic Reprogramming During Malignant Transformation of Chronic Colitis

“…However, the triad stress responses of nucleus, ER, and mitochondria also induce oxidative damage, DNA mutations, angiogenesis, and metabolic changes, if sustained in chronic inflammation, conducive to cell malignant transformation and cancer growth (9)(10)(11). The inhibition of ER stress by chemical compounds has demonstrated effective in the preclinical and clinical trials of multiple tumors (12,13).…”