When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues on the specificity and use of GSK2606414 and GSK2656157

Rojas‐Rivera, Diego; Delvaeye, Tinneke; Roelandt, Ria; Nerinckx, Wim; Augustyns, Koen; Vandenabeele, Peter; Bertrand, Mathieu J.M.

doi:10.1038/cdd.2017.58

Cited by 158 publications

(129 citation statements)

References 43 publications

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“…Interestingly, oral administration of GSK2606414 alleviated neurodegeneration in tau transgenic mice [140]. However, a recent report suggested that GSK2606414 has a higher affinity for RIP kinases, in addition to generating serious side effects due to pancreatic toxicity [141]. In contrast, the administration of ISRIB provided neuroprotection in a model of prion disease while not triggering any pancreatic toxicity [50].…”

Section: Targeting the Upr For Therapeutic Inerventionmentioning

confidence: 99%

Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease

2017

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Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by synaptic dysfunction and accumulation of abnormal aggregates formed by amyloid-β peptides or phosphorylated tau proteins. Accumulating evidence suggests that alterations in the buffering capacity of the proteostasis network are a salient feature of AD. The endoplasmic reticulum (ER) is the main compartment involved in protein folding and secretion and is drastically affected in AD neurons. ER stress triggers the activation of the unfolded protein response (UPR), a signal transduction pathway that enforces adaptive programs to recover homeostasis or trigger apoptosis of irreversibly damaged cells. Experimental manipulation of specific UPR signaling modules in preclinical models of AD has revealed a key role of this pathway in regulating protein misfolding and neurodegeneration. Recent studies suggest that the UPR also influences synaptic plasticity and memory through ER stress-independent mechanisms. Consequently, targeting of the UPR in AD is emerging as an interesting therapeutic approach to modify the two pillars of AD, protein misfolding and synaptic failure. Here, we review the functional role of ER stress signaling in AD, discussing the complex involvement of the pathway in controlling neuronal survival, the amyloid cascade, neurodegeneration and synaptic function. Recent intervention efforts to target the UPR with pharmacological and gene therapy strategies are also discussed.

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Section: Targeting the Upr For Therapeutic Inerventionmentioning

confidence: 99%

Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease

2017

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“…Conversely, GSK-PKI treatment mildly increased apoptosis and dampened growth rate in cultured INS-1 cells (Fig 4B and C). This discrepancy may stem from pathway compensation in PERK KO cells or off-target GSK-PKI effects (48), but the aggregate effect is modest under low ER stress.…”

Section: Induced Apoptosis In Vitromentioning

confidence: 99%

Parallel signaling through IRE1α and PERK regulates pancreatic neuroendocrine tumor growth and survival

Moore

Thamsen³

et al. 2019

Preprint

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Master regulators of the unfolded protein response (UPR)—IRE1α and PERK— promote adaptation or apoptosis depending on levels of endoplasmic reticulum (ER) stress. While the UPR is activated in many cancers, its effects on tumor growth remain unclear. Derived from endocrine cells, pancreatic neuroendocrine tumors (PanNETs) universally hypersecrete one or more peptide hormones, likely sensitizing these cells to high ER protein-folding stress. For the nearly 1,500 Americans diagnosed with PanNETs annually, surgery is the only potentially curative treatment; however the five-year survival is extremely low for those who develop metastatic disease. To assess whether targeting the UPR is a viable therapeutic strategy, we analyzed human PanNET samples and found evidence of elevated ER stress and UPR activation. We then used genetic and pharmacologic approaches to modulate IRE1α and PERK in cultured cells and xenograft and spontaneous genetic (RIP-Tag2) mouse models of PanNETs. We found that UPR signaling is optimized for adaptation and that inhibiting either IRE1α or PERK leads to hyperactivation and apoptotic signaling through the reciprocal arm, thereby halting tumor growth and survival. Our results provide a strong rationale for therapeutically targeting the UPR in PanNETs and other cancers experiencing elevated ER stress.SignificanceThe unfolded protein response (UPR) is upregulated in human pancreatic neuroendocrine tumors and its genetic or pharmacological inhibition significantly reduces tumor growth in preclinical models, providing strong rationale for targeting the UPR in neoplasms with elevated ER stress.

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“…PERK inhibition by these small molecules induced pancreatic β-cell toxicity, similar to what has been seen in the PERK knockout mouse, indicating more sophisticated methods to deliver these inhibitors are required (140).…”

Section: Amg Perk44mentioning

confidence: 77%

The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities

Song

Riesenberg

et al. 2020

Front. Immunol.

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The endoplasmic reticulum (ER) is an organelle equipped with mechanisms for proper protein folding, trafficking, and degradation to maintain protein homeostasis in the secretory pathway. As a defense mechanism, perturbation of ER proteostasis by ER stress agents activates a cascade of signaling pathways from the ER to the nucleus known as unfolded protein response (UPR). The primary goal of UPR is to induce transcriptional and translational programs to restore ER homeostasis for cell survival. As such, defects in UPR signaling have been implicated as a key contributor to multiple diseases including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer. Growing evidence support the critical role of ER stress in regulating the fate as well as the magnitude of the immune response. Moreover, the availability of multiple UPR pharmacological inhibitors raises the hope that targeting UPR can be a new strategy for immune modulation and immunotherapy of diseases. This paper reviews the principal mechanisms by which ER stress affects immune cell biology and function, with a focus of discussion on UPR-associated immunopathology and the development of potential ER stress-targeted therapeutics.Frontiers in Immunology | www.frontiersin.org Conflict of Interest: ZL serves as member of scientific advisory board for Alphamab and Henlius Biotech and has a sponsored research agreement with Bristol-Myers Squibb.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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When PERK inhibitors turn out to be new potent RIPK1 inhibitors: critical issues on the specificity and use of GSK2606414 and GSK2656157

Cited by 158 publications

References 43 publications

Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease

Emerging roles of ER stress in the etiology and pathogenesis of Alzheimer's disease

Parallel signaling through IRE1α and PERK regulates pancreatic neuroendocrine tumor growth and survival

The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities

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