Tumor cells rely on the thiol oxidoreductase PDI for PERK signaling in order to survive ER stress

Kranz, Philip; Sänger, Christopher; Wolf, Alexandra; Baumann, J; Metzen, Eric; Baumann, M.; Göpelt, Kirsten; Brockmeier, Ulf

doi:10.1038/s41598-020-72259-1

Cited by 7 publications

(5 citation statements)

References 48 publications

(48 reference statements)

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“…According to the previous researches, protein disulfide isomerase (PDI) family members play an essential role in ER stress activation (Hsu et al, 2019;Zhang et al, 2019). The P4HB (also known as PDIA1) and PDIA4, which were chosen from the six-gene signature, belong to the protein PDI protein family and have been proved to be related to ER stress activation in human cancers (Joo et al, 2007;Kranz et al, 2017;Winship et al, 2017;Liu et al, 2019;Wang et al, 2020), especially the PERK signaling pathway (Kranz et al, 2017(Kranz et al, , 2020. Serval recent researches has pointed out that P4HB and PDIA4 correlated with the malignant progression of glioma, but these conclusions have not been sufficiently verified by in vitro experiments (Zou et al, 2018;Li et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of the Clinical and Biological Significances of Endoplasmic Reticulum Stress in Diffuse Gliomas

Huang

Wang

et al. 2021

Front. Cell Dev. Biol.

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BackgroundAs a critical organelle for protein and lipid synthesis, the dysfunction of endoplasmic reticulum has a significant impact on multiple biological processes of cells. Thus, in this study, we constructed an ER stress-related risk signature to investigate the functional roles of ER stress in gliomas.MethodsA total of 626 samples from TCGA RNA-seq dataset (training cohort) and 310 samples from CGGA RNA-seq dataset (validation cohort) were enrolled in this study. Clinical information and genomic profiles were also obtained. The ER stress signature was developed by the LASSO regression model. The prognostic value of the risk signature was evaluated by Cox regression, Kaplan-Meier and ROC Curve analyses. Bioinformatics analysis and experiment in vitro were performed to explore the biological implication of this signature.ResultsWe found that the ER stress-related signature was tightly associated with major clinicopathological features and genomic alterations of gliomas. Kaplan-Meier curve and Cox regression analysis indicated that ER stress activation was an independent prognostic factor for patients with glioma. Besides, we also constructed an individualized prognosis prediction model through Nomogram and ROC Curve analysis. Bioinformatics analysis suggested that ER stress activation also promoted the malignant progression of glioma and participated in the regulation of tumor immune microenvironment, especially the infiltration of macrophages in M2 phase. These results were further validated in IHC analysis and cell biology experiments.ConclusionThe ER stress activation had a high prognostic value and could serve as a promising target for developing individualized treatment of glioma.

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Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of the Clinical and Biological Significances of Endoplasmic Reticulum Stress in Diffuse Gliomas

Huang

Wang

et al. 2021

Front. Cell Dev. Biol.

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“…However, TGFβ1 alone caused an increase in total and phosphorylated PERK; and increasing levels of HRas did not meaningfully regulate PERK activation as previously shown 26 (Figures 2B and ). Similarly, while TGFβ1 increased Perk , Pdia4 , and Pdia5 mRNA expression (Figure 2C) suggesting TGFβ1‐dependent activation of PERK signaling in these keratinocytes, 53 no additional effect of HRas on expression of these genes was observed (Figure ). Furthermore, Western blot showed higher total PERK, phospho‐eIF2α, ATF4, and CHOP expression even at a low dose of 0.25 ng/ml TGFβ1.…”

Section: Resultsmentioning

confidence: 85%

“…Similarly, while TGFβ1 increased Perk, Pdia4, and Pdia5 mRNA expression (Figure 2C) suggesting TGFβ1-dependent activation of PERK signaling in these keratinocytes, 53 no additional effect of HRas on expression of these genes was observed (Figure S3B). Furthermore, Western blot showed higher total PERK, phospho-eIF2α, ATF4, and CHOP expression even at a low dose of 0.25 ng/ml TGFβ1.…”

Section: Tgfβ1 Activates Perk Signaling In Keratinocytesmentioning

confidence: 87%

TGFβ1 regulates HRas‐mediated activation of IRE1α through the PERK‐RPAP2 axis in keratinocytes

Mogre

Blazanin

Walsh

et al. 2022

Molecular Carcinogenesis

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Transforming Growth Factor β1 (TGFβ1) is a critical regulator of tumor progression in response to HRas. Recently, TGFβ1 has been shown to trigger ER stress in many disease models; however, its role in oncogene‐induced ER stress is unclear. Oncogenic HRas induces the unfolded protein response (UPR) predominantly via the Inositol‐requiring enzyme 1α (IRE1α) pathway to initiate the adaptative responses to ER stress, with importance for both proliferation and senescence. Here, we show a role of the UPR sensor proteins IRE1α and (PKR)‐like endoplasmic reticulum kinase (PERK) to mediate the tumor‐suppressive roles of TGFβ1 in mouse keratinocytes expressing mutant forms of HRas. TGFβ1 suppressed IRE1α phosphorylation and activation by HRas both in in vitro and in vivo models while simultaneously activating the PERK pathway. However, the increase in ER stress indicated an uncoupling of ER stress and IRE1α activation by TGFβ1. Pharmacological and genetic approaches demonstrated that TGFβ1‐dependent dephosphorylation of IRE1α was mediated by PERK through RNA Polymerase II Associated Protein 2 (RPAP2), a PERK‐dependent IRE1α phosphatase. In addition, TGFβ1‐mediated growth arrest in oncogenic HRas keratinocytes was partially dependent on PERK‐induced IRE1α dephosphorylation and inactivation. Together, these results demonstrate a critical cross‐talk between UPR proteins that is important for TGFβ1‐mediated tumor suppressive responses.

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“…PERK, encoded by EIF2AK3 , is a type I membrane protein located in the ER and could be activated under ER stress caused by malfolded proteins. The activated PERK could phosphorylate and inactivate the alpha subunit of eukaryotic translation–initiation factor 2 (elF2α), resulting in an effective reduction of translational initiation and repression of protein synthesis ( Kranz et al, 2020 ). In addition, PERK was gradually proved to be involved in the regulation of mitochondrial function, serving as a bridge between mitochondrial metabolism and ER homeostasis ( Fan and Simmen, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

ER Stress–Related Genes EIF2AK3, HSPA5, and DDIT3 Polymorphisms are Associated With Risk of Lung Cancer

et al. 2022

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Objective: This study aimed to evaluate the associations between endoplasmic reticulum (ER) stress–related genes EIF2AK3/PERK, HSPA5/GRP78, and DDIT3/CHOP polymorphisms and the risk of lung cancer.Methods: Six single-nucleotide polymorphisms (SNPs) of EIF2AK3, HSPA5, and DDIT3 were genotyped in 620 cases and 620 controls using a MassARRAY platform.Results: The minor allele A of rs6750998 was a protective allele against the risk of lung cancer (p < 0.001), while the minor alleles of rs867529, rs391957, and rs697221 were all risk alleles that may lead to multiplied risk of the disease (rprs867529 = 0.002; prs391957 = 0.015; prs697221 < 0.001). Moreover, the rs6750998-TA/AA genotypes were protective genotypes against the risk of lung cancer (p = 0.005); however, the rs867529-GC/CC, rs391957-CC, and rs697221-GA/AA genotypes were associated with elevated lung cancer risk (prs867529 = 0.003, prs391957 = 0.028, and prs697221 = 0.0001). In addition, EIF2AK3-rs6750998 was associated with a decreased risk of lung cancer under dominant, recessive, and log-additive models (p < 0.05). By contrast, the EIF2AK3-rs867529 was correlated with an increased risk of the disease under dominant and log-additive models (p = 0.001). Moreover, HSPA5-rs391957 was related to an elevated risk of the disease under recessive and log-additive models (p < 0.02). DDIT3-rs697221 was identified to have a significant association with the risk of lung cancer under all three genetic models (p < 0.01).Conclusion: Our results provide new insights on the role of the ER stress–related genes EIF2AK3, HSPA5, and DDIT3 polymorphisms for lung cancer risk.

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Tumor cells rely on the thiol oxidoreductase PDI for PERK signaling in order to survive ER stress

Cited by 7 publications

References 48 publications

Comprehensive Analysis of the Clinical and Biological Significances of Endoplasmic Reticulum Stress in Diffuse Gliomas

Comprehensive Analysis of the Clinical and Biological Significances of Endoplasmic Reticulum Stress in Diffuse Gliomas

TGFβ1 regulates HRas‐mediated activation of IRE1α through the PERK‐RPAP2 axis in keratinocytes

ER Stress–Related Genes EIF2AK3, HSPA5, and DDIT3 Polymorphisms are Associated With Risk of Lung Cancer

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