The multiple roles of the unfolded protein response regulator IRE1α in cancer

Abstract

Cancer is associated with a number of conditions such as hypoxia, nutrient deprivation, cellular redox, and pH changes that result in accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) and trigger a stress response known as the unfolded protein response (UPR). The UPR is a conserved cellular survival mechanism mediated by the ER transmembrane proteins activating transcription factor 6, protein kinase‐like endoplasmic reticulum kinase, and inositol‐requiring enzyme 1α (IRE1α) that act to resolve ER stress and promote cell survival. IRE1α is a kinase/endoribonuclease (RNase) with multiple activities including unconventional splicing of the messenger RNA (mRNA) for the transcription factor X‐Box Binding Protein 1 (XBP1), degradation of other mRNAs in a process called regulated IRE1α‐dependent decay (RIDD) and activation of a pathway leading to c‐Jun N‐terminal kinase phosphorylation. Each of these outputs plays a role in the adaptive and cell death responses to ER stress. Many studies indicate an important role for XBP1 and RIDD functions in cancer and new studies suggest that these two functions of the IRE1α RNase can have opposing functions in the early and later stages of cancer pathogenesis. Finally, as more is learned about the context‐dependent role of IRE1α in cancer development, specific small molecule inhibitors and activators of IRE1α could play an important role in counteracting the protective shield provided by ER stress signaling in cancer cells.

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

“…Furthermore, the length of drug exposure should be taken into consideration due to the dynamic and time-dependent cytotoxic or cytoprotective effects of the UPR [158]. A further layer of complexity is added by the interactions between leukemic cells and the BM microenvironment, especially in light of the transmissibility of ER stress and UPR between cells via extracellular vesicles, that can transport mRNAs, miRs, and misfolded proteins, thereby disrupting ER homeostasis of the recipient cells [67,160]. ER stress transmitted by leukemic cells via extracellular vesicles results in changes in the composition and function of BM microenvironmental cells, leading to the osteogenic differentiation of BM MSCs [80].…”

“…Although RIDD cleaves RNA at an XBP1-like consensus element (CUGCAG), its activity is divergent from canonical XBP1 cleavage [66]. RIDD has been associated with the degradation of many mRNA, rRNAs, and microRNAs (miRs), thereby either preserving ER homeostasis or inducing apoptosis [67]. For example, during RIDD, IRE1α cleaves and inactivates a selected subset of anti-CASP2 gene pre-miRs (miR-17, miR-34a, miR-96, and miR-125b).…”

“…Consequently, there is an up-regulation of the CASP2 gene and the initiation of the intrinsic apoptotic pathway [68]. IRE1α also acts as the driver of signals leading to increased expression of proapoptotic CHOP [67] and to the activation of the JNK pathway that facilitates cell death [69]. Therefore, IRE1α signaling plays a bifurcated role in determining cell fate during UPR.…”

Calreticulin promotes EMT in pancreatic cancer via mediating Ca2+ dependent acute and chronic endoplasmic reticulum stress

“…Chronic ERS produces endogenous or exogenous damage to cells and triggers an UPR response. IRE1α is the most evolutionally conserved one in UPR [65]. As an ER type I transmembrane protein, the role of IRE1α in cancers is no longer simply considered as an oncogene or tumor suppressor, but a key component of cell fate switch, depending on different cancer types [66].…”

Natural killer cells in Hodgkin Lymphoma

“…In a healthy individual, the IRE1-XBP1 pathway operates within the UPR system as a physiological response to ER stress triggered by physiological stimuli such as oxidative stress, glucose depletion and hypoxia. These processes lead to accumulation of misfolded and unfolded proteins in cells which in turn induce IRE1 auto-phosphorylation followed by dimerization and activation of endonuclease activity to splice out a 26-nucleotide intron from XBP1 mRNA, leadings to generation of XBP1s [205]. This molecule is a potent transcription factor involved in ER stress mitigation by regulation of a range of chaperones, foldases and glycotransferases [204] Notably, investigations of the IRE1-XBP1 pathway in circulating pNK cells from patients with HL suggest that the pathway is not activated in these cells in response to HRS cells.…”