Pharmacological Targeting of IRE1 in Cancer

Raymundo, Diana Pelizzari; Doultsinos, Dimitrios; Guillory, X.; Carlesso, Antonio; Eriksson, Leif A.; Chevet, Éric

doi:10.1016/j.trecan.2020.07.006

Cited by 71 publications

(70 citation statements)

References 80 publications

(70 reference statements)

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“…Despite the fact that IRE1α's molecular activities are mostly related to facilitating cellular survival, during irrevocable ER stress, this enzyme can also contribute to accumulation of proinflammatory and apoptotic factors [52]. Thus, gaining control over IRE1α's activities with small molecules remains a promising approach to improving cancer treatments by inhibiting IRE1α activity during the early stages of tumorigenesis [53][54][55] and by preventing tumor progression and metastasis either by utilizing proapoptotic abilities of this enzyme [4] or inducing apoptosis through other signaling pathways such as PERK. Nevertheless, most studies focus on inhibiting IRE1α activity to impair the adaptation of tumor cells to their cellular stressors.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, most studies focus on inhibiting IRE1α activity to impair the adaptation of tumor cells to their cellular stressors. Currently, numerous compounds has been shown to be highly selective in preventing IRE1α kinase, RNAse or both activities and are characterized by EC 50 values ranging from 0.02 to 20 µM (reviewed in [4]). Furthermore, molecules such as astoyocamycin, doxorubicin, quinotrierixin, and trierixin were shown to inhibit IRE1α/ XBP1s activity in vitro and in vivo despite no clear determination of their mechanism of their action with IRE1α [4].…”

Section: Discussionmentioning

confidence: 99%

“…Although the all three UPR sensors provide appealing therapeutic candidates, IRE1α activity has been a major focus because it promotes a protumoral phenotype in several cancers and furthermore, elevated levels of IRE1α are associated with poor cancer prognosis (reviewed in [4,5]). IRE1α is ubiquitously expressed and displays both serine/ threonine kinase and endoribonuclease (RNase) activities.…”

mentioning

confidence: 99%

“…Given that dysregulation of IREα and XBP1s levels are associated with poor cancer patient survival and drug resistance [14][15][16][17][18][19] and IRE1's kinase and endoribonuclease activities are required for generating XBP1s, IRE1α has become an attractive therapeutic targets for novel anticancer therapies. Although numerous small molecules that inhibit IRE1α activity has been developed, their use in cancer therapy remains limited [4,5], and therefore the search for new drug candidates that inhibit IRE1α activity is clearly needed. In this study, we demonstrate that triazoloacridone C-1305, a microtubule stabilizing agent that also has topoisomerase II inhibitory activity [20,21], efficiently prevents XBP1 splicing, therefore suggesting that C-1305 inhibits IRE1's endoribonuclease activity.…”

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confidence: 99%

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Triazoloacridone C-1305 impairs XBP1 splicing by acting as a potential IRE1α endoribonuclease inhibitor

et al. 2021

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Inositol requiring enzyme 1 alpha (IRE1α) is one of three signaling sensors in the unfolding protein response (UPR) that alleviates endoplasmic reticulum (ER) stress in cells and functions to promote cell survival. During conditions of irrevocable stress, proapoptotic gene expression is induced to promote cell death. One of the three signaling stressors, IRE1α is an serine/threonine-protein kinase/endoribonuclease (RNase) that promotes nonconventional splicing of XBP1 mRNA that is translated to spliced XBP1 (XBP1s), an active prosurvival transcription factor. Interestingly, elevated IRE1α and XBP1s are both associated with poor cancer survival and drug resistance. In this study, we used next-generation sequencing analyses to demonstrate that triazoloacridone C-1305, a microtubule stabilizing agent that also has topoisomerase II inhibitory activity, dramatically decreases XBP1s mRNA levels and protein production during ER stress conditions, suggesting that C-1305 does this by decreasing IRE1α’s endonuclease activity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Triazoloacridone C-1305 impairs XBP1 splicing by acting as a potential IRE1α endoribonuclease inhibitor

et al. 2021

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“…The UPR/ISR is a being investigated for cancer therapy targets, for example, IRE1 inhibitors are being developed (Raymundo et al., 2020) for use in breast cancer, while GRP78 inhibitors displayed promise in the treatment of melanoma (Bu & Diehl, 2016b) and in increasing sensitivity of melanoma cells to temozolomide (Ryabaya et al., 2018).…”

Section: The Upr/isr In Disease Pathologymentioning

confidence: 99%

The unfolded protein and integrated stress response in melanoma and vitiligo

Manga

Choudhury

2020

Pigment Cell Melanoma Res

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Epidermal melanocytes are constantly exposed to environmental stressors such as ultraviolet light (UV) and chemotoxins. Several evolutionarily conversed survival mechanisms are deployed to ensure melanocyte recovery after damage including the unfolded protein response (UPR) and integrated stress response (ISR). The UPR/ISR promote restoration of homeostasis, by modulating transcription and translation as well as activating nuclear factor erythroid 2‐related factor 2 (NRF2)‐mediated antioxidant activity. If repair fails, the UPR/ISR either stimulate cell death, or adaptation that can lead to survival of damaged cells and promote disease. For example, the UPR/ISR may support melanomagenesis by allowing UV‐damaged, mutated cells to survive and adapt to a hostile tumor microenvironment that subjects cells to hypoxia, nutrient deprivation, and sub‐optimal pH. The UPR and ISR can also promote transcriptional changes that support tumor growth and/or metastasis. Furthermore, these pathways may also underlie acquisition of chemoresistance and modulation of protein expression that alters the efficacy of immunotherapies. UPR activation has also been implicated in the pathogenesis of vitiligo and may promote increased expression of chemokines such as interleukin 6 and interleukin 8 that trigger an autoimmune response against melanocytes. We herein review the potential roles of the UPR/ISR in the etiology of melanoma and vitiligo.

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Endoplasmic reticulum stress in diseases

Liu,

Xu,

et al. 2024

MedComm

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The endoplasmic reticulum (ER) is a key organelle in eukaryotic cells, responsible for a wide range of vital functions, including the modification, folding, and trafficking of proteins, as well as the biosynthesis of lipids and the maintenance of intracellular calcium homeostasis. A variety of factors can disrupt the function of the ER, leading to the aggregation of unfolded and misfolded proteins within its confines and the induction of ER stress. A conserved cascade of signaling events known as the unfolded protein response (UPR) has evolved to relieve the burden within the ER and restore ER homeostasis. However, these processes can culminate in cell death while ER stress is sustained over an extended period and at elevated levels. This review summarizes the potential role of ER stress and the UPR in determining cell fate and function in various diseases, including cardiovascular diseases, neurodegenerative diseases, metabolic diseases, autoimmune diseases, fibrotic diseases, viral infections, and cancer. It also puts forward that the manipulation of this intricate signaling pathway may represent a novel target for drug discovery and innovative therapeutic strategies in the context of human diseases.

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Pharmacological Targeting of IRE1 in Cancer

Cited by 71 publications

References 80 publications

Triazoloacridone C-1305 impairs XBP1 splicing by acting as a potential IRE1α endoribonuclease inhibitor

Triazoloacridone C-1305 impairs XBP1 splicing by acting as a potential IRE1α endoribonuclease inhibitor

The unfolded protein and integrated stress response in melanoma and vitiligo

Endoplasmic reticulum stress in diseases

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