New small molecule inhibitors of UPR activation demonstrate that PERK, but not IRE1α signaling is essential for promoting adaptation and survival to hypoxia

Cojocari, Dan; Vellanki, Ravi N.; Sit, Brandon; Uehling, David; Koritzinsky, Marianne; Wouters, Bradly G.

doi:10.1016/j.radonc.2013.06.005

Cited by 39 publications

(23 citation statements)

References 33 publications

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“…On the other hand, at more advanced stages of tumor progression, during which cells are exposed to more severe stressors, GRP78 suppresses caspase 7 activation and interacts with ER stress-induced protein chaperones such as clusterin to promote cell survival and further tumor development [61]. The PERK-eIF2 α -ATF4 pathway is often activated by the hypoxic condition in solid tumors [62–64], which activates angiogenic genes, vascular endothelial growth factor (VEGF), type 1 collagen inducible protein, and autophagosome components such as LC3, ensuring cell survival over hypoxia-induced ER stress [65–67]. Prolonged expression and activation of ATF6 increase the Rheb-mTOR signaling pathway and also enhance tumor cell survival [68].…”

Section: Emerging Role Of Aerr In Liver Tumorigenesis and Hccmentioning

confidence: 99%

New Insights into the Pathogenesis of Alcohol-Induced ER Stress and Liver Diseases

Cheng

2014

International Journal of Hepatology

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Alcohol-induced liver disease increasingly contributes to human mortality worldwide. Alcohol-induced endoplasmic reticulum (ER) stress and disruption of cellular protein homeostasis have recently been established as a significant mechanism contributing to liver diseases. The alcohol-induced ER stress occurs not only in cultured hepatocytes but also in vivo in the livers of several species including mouse, rat, minipigs, zebrafish, and humans. Identified causes for the ER stress include acetaldehyde, oxidative stress, impaired one carbon metabolism, toxic lipid species, insulin resistance, disrupted calcium homeostasis, and aberrant epigenetic modifications. Importance of each of the causes in alcohol-induced liver injury depends on doses, duration and patterns of alcohol exposure, genetic disposition, environmental factors, cross-talks with other pathogenic pathways, and stages of liver disease. The ER stress may occur more or less all the time during alcohol consumption, which interferes with hepatic protein homeostasis, proliferation, and cell cycle progression promoting development of advanced liver diseases. Emerging evidence indicates that long-term alcohol consumption and ER stress may directly be involved in hepatocellular carcinogenesis (HCC). Dissecting ER stress signaling pathways leading to tumorigenesis will uncover potential therapeutic targets for intervention and treatment of human alcoholics with liver cancer.

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Section: Emerging Role Of Aerr In Liver Tumorigenesis and Hccmentioning

confidence: 99%

New Insights into the Pathogenesis of Alcohol-Induced ER Stress and Liver Diseases

Cheng

2014

International Journal of Hepatology

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“…Cojocari et al [32] recently suggested that the PERK signaling arm is uniquely important for promoting adaptation and survival during hypoxia-induced ER stress. Yet, other reports suggest that UPR mediated cell adaptation is not due to selective UPR sensor activation, but most likely reflects changes in protein composition or mRNA stability of adapted cells [33].…”

Section: Discussionmentioning

confidence: 99%

N-Octanoyl Dopamine Treatment of Endothelial Cells Induces the Unfolded Protein Response and Results in Hypometabolism and Tolerance to Hypothermia

et al. 2014

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AimN-acyl dopamines (NADD) are gaining attention in the field of inflammatory and neurological disorders. Due to their hydrophobicity, NADD may have access to the endoplasmic reticulum (ER). We therefore investigated if NADD induce the unfolded protein response (UPR) and if this in turn influences cell behaviour.MethodsGenome wide gene expression profiling, confirmatory qPCR and reporter assays were employed on human umbilical vein endothelial cells (HUVEC) to validate induction of UPR target genes and UPR sensor activation by N-octanoyl dopamine (NOD). Intracellular ATP, apoptosis and induction of thermotolerance were used as functional parameters to assess adaptation of HUVEC.ResultsNOD, but not dopamine dose dependently induces the UPR. This was also found for other synthetic NADD. Induction of the UPR was dependent on the redox activity of NADD and was not caused by selective activation of a particular UPR sensor. UPR induction did not result in cell apoptosis, yet NOD strongly impaired cell proliferation by attenuation of cells in the S-G2/M phase. Long-term treatment of HUVEC with low NOD concentration showed decreased intracellular ATP concentration paralleled with activation of AMPK. These cells were significantly more resistant to cold inflicted injury.ConclusionsWe provide for the first time evidence that NADD induce the UPR in vitro. It remains to be assessed if UPR induction is causally associated with hypometabolism and thermotolerance. Further pharmacokinetic studies are warranted to address if the NADD concentrations used in vitro can be obtained in vivo and if this in turn shows therapeutic efficacy.

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“…Accumulation of unfolded or misfolded proteins in the ER activates the unfolded protein response (UPR), where three sensors of ER stress (PERK, IRE1 and ATF6) regulate transcription and translation to increase folding capacity and protect against cell death [35][36][37] . The ER stress sensor PERK is particularly important for cellular tolerance to severe hypoxia 36,[38][39][40] . Upon activation, it phosphorylates the mRNA translation factor eIF2α that shuts down overall protein synthesis (Figure 2) 41 .…”

Section: Adaptationmentioning

confidence: 99%

Hypoxia and Predicting Radiation Response

Hill

Bristow

Fyles

et al. 2015

Seminars in Radiation Oncology

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New small molecule inhibitors of UPR activation demonstrate that PERK, but not IRE1α signaling is essential for promoting adaptation and survival to hypoxia

Cited by 39 publications

References 33 publications

New Insights into the Pathogenesis of Alcohol-Induced ER Stress and Liver Diseases

New Insights into the Pathogenesis of Alcohol-Induced ER Stress and Liver Diseases

N-Octanoyl Dopamine Treatment of Endothelial Cells Induces the Unfolded Protein Response and Results in Hypometabolism and Tolerance to Hypothermia

Hypoxia and Predicting Radiation Response

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