Pancreatic Endoplasmic Reticulum Kinase Activation Promotes Medulloblastoma Cell Migration and Invasion through Induction of Vascular Endothelial Growth Factor A

Jamison, Stephanie; Lin, Yifeng; Lin, Wensheng

doi:10.1371/journal.pone.0120252

Cited by 31 publications

(20 citation statements)

References 52 publications

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“…Consistent with this latter role, PERK promotes tumourigenesis (Bobrovnikova-Marjon et al, 2010 ) and PERK-deficient cells display a reduced ability to form solid tumors in nude mice (Spiotto et al, 2010 ). More recently, a new role for PERK signaling in promoting cancer cell migration and invasion was proposed based on experiments evaluating the effects of moderate PERK activation on medulloblastoma cell migration and invasion (Jamison et al, 2015 ). Overall, these observations support the idea that, besides its classical role in UPR and apoptosis, following H. pylori infection, PERK expression also promotes human gastric cell migration and invasion and thus the acquisition of an aggressive phenotype.…”

Section: Endoplasmic Reticulum Stress and The Unfolded Protein Responmentioning

confidence: 99%

Helicobacter pylori and Gastric Cancer: Adaptive Cellular Mechanisms Involved in Disease Progression

Díaz

Valenzuela-Valderrama

et al. 2018

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Helicobacter pylori (H. pylori) infection is the major risk factor associated with the development of gastric cancer. The transition from normal mucosa to non-atrophic gastritis, triggered primarily by H. pylori infection, initiates precancerous lesions which may then progress to atrophic gastritis and intestinal metaplasia. Further progression to dysplasia and gastric cancer is generally believed to be attributable to processes that no longer require the presence of H. pylori. The responses that develop upon H. pylori infection are directly mediated through the action of bacterial virulence factors, which drive the initial events associated with transformation of infected gastric cells. Besides genetic and to date poorly defined environmental factors, alterations in gastric cell stress-adaptive mechanisms due to H. pylori appear to be crucial during chronic infection and gastric disease progression. Firstly, H. pylori infection promotes gastric cell death and reduced epithelial cell turnover in the majority of infected cells, resulting in primary tissue lesions associated with an initial inflammatory response. However, in the remaining gastric cell population, adaptive responses are induced that increase cell survival and proliferation, resulting in the acquisition of potentially malignant characteristics that may lead to precancerous gastric lesions. Thus, deregulation of these intrinsic survival-related responses to H. pylori infection emerge as potential culprits in promoting disease progression. This review will highlight the most relevant cellular adaptive mechanisms triggered upon H. pylori infection, including endoplasmic reticulum stress and the unfolded protein response, autophagy, oxidative stress, and inflammation, together with a subsequent discussion on how these factors may participate in the progression of a precancerous lesion. Finally, this review will shed light on how these mechanisms may be exploited as pharmacological targets, in the perspective of opening up new therapeutic alternatives for non-invasive risk control in gastric cancer.

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Section: Endoplasmic Reticulum Stress and The Unfolded Protein Responmentioning

confidence: 99%

Helicobacter pylori and Gastric Cancer: Adaptive Cellular Mechanisms Involved in Disease Progression

Díaz

Valenzuela-Valderrama

et al. 2018

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“…The PERK and ATF6 arms of the UPR also induce ADAM17, a member of the ADAM (a disintegrin and metalloproteinase) family that is associated with tumor initiation and progression (75). In other brain tumors such as medulloblastoma, PERK activation increases VEGFA expression and is associated with enhanced cell migration through VEGFR2 signaling (76). However, no evidence has been reported so far that PERK promotes GBM angiogenesis and invasion.…”

Section: Upr-induced Transcription Factors In Cancer-associated Signamentioning

confidence: 99%

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

et al. 2017

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“…Genetic studies have demonstrated that PERK is essential in supporting tumor growth and progression via diverse mechanisms, including stimulation of angiogenesis (7)(8)(9)(10)(11)(12), potential effects on antitumor immunity (13,14), and direct increase in cancer cell viability by altering its metabolic status (15), promoting survival autophagy (16)(17)(18), and induction of prosurvival microRNAs (19). Accordingly, development of novel, potent, and selective PERK inhibitors as a means to treat cancers has been proposed (20,21).…”

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confidence: 99%

Type I interferons mediate pancreatic toxicities of PERK inhibition

Yu¹,

Zhao²,

Gui³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The great preclinical promise of the pancreatic endoplasmic reticulum kinase (PERK) inhibitors in neurodegenerative disorders and cancers is marred by pancreatic injury and diabetic syndrome observed in PERK knockout mice and humans lacking PERK function and suffering from Wolcott-Rallison syndrome. PERK mediates many of the unfolded protein response (UPR)-induced events, including degradation of the type 1 interferon (IFN) receptor IFNAR1 in vitro. Here we report that whole-body or pancreas-specific Perk ablation in mice leads to an increase in IFNAR1 protein levels and signaling in pancreatic tissues. Concurrent IFNAR1 deletion attenuated the loss of PERKdeficient exocrine and endocrine pancreatic tissues and prevented the development of diabetes. Experiments using pancreas-specific Perk knockouts, bone marrow transplantation, and cultured pancreatic islets demonstrated that stabilization of IFNAR1 and the ensuing increased IFN signaling in pancreatic tissues represents a major driver of injury triggered by Perk loss. Neutralization of IFNAR1 prevented pancreatic toxicity of PERK inhibitor, indicating that blocking the IFN pathway can mitigate human genetic disorders associated with PERK deficiency and help the clinical use of PERK inhibitors.T umor microenvironment-associated deficit in oxygen and nutrients activate numerous pathways that aid cancer and tumor stroma cells by increasing their ability to survive, withstand anticancer therapies, and ultimately select for more aggressive and viable clones capable of metastasizing (1). Activation of the unfolded protein response (UPR) plays a central role in these processes (2). Three branches of this response include stimulation of activating transcription factor-6 and activation of two kinases, inositol requiring enzyme 1α/β and the eukaryotic translation initiation factor 2-alpha kinase 3 [also termed double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase, or pancreatic endoplasmic reticulum kinase (PERK)]. The latter kinase contributes to phosphorylation of the eukaryotic translation initiation factor 2-alpha and controls the rate of global translation and noncanonical induction of specific proteins that help cope with stress (reviewed in ref. 2).Among three main UPR pathways, signaling through PERK has received the most attention for its central role in cancer (3-6). Genetic studies have demonstrated that PERK is essential in supporting tumor growth and progression via diverse mechanisms, including stimulation of angiogenesis (7-12), potential effects on antitumor immunity (13,14), and direct increase in cancer cell viability by altering its metabolic status (15), promoting survival autophagy (16-18), and induction of prosurvival microRNAs (19). Accordingly, development of novel, potent, and selective PERK inhibitors as a means to treat cancers has been proposed (20, 21). Several PERK inhibitors have shown promising results in various preclinical tumor models (22-24). Furthermore, some of these inhibitors can protect against the prion-...

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Pancreatic Endoplasmic Reticulum Kinase Activation Promotes Medulloblastoma Cell Migration and Invasion through Induction of Vascular Endothelial Growth Factor A

Cited by 31 publications

References 52 publications

Helicobacter pylori and Gastric Cancer: Adaptive Cellular Mechanisms Involved in Disease Progression

Helicobacter pylori and Gastric Cancer: Adaptive Cellular Mechanisms Involved in Disease Progression

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

Type I interferons mediate pancreatic toxicities of PERK inhibition

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