PDI is an essential redox-sensitive activator of PERK during the unfolded protein response (UPR)

Kranz, Philip; Neumann, Fabian; Wolf, Alexandra; Classen, Fabian; Pompsch, Mosche; Ocklenburg, Tobias; Baumann, J; Janke, Kirsten; Baumann, M.; Goepelt, Kirsten; Riffkin, Helena; Metzen, Eric; Brockmeier, Ulf

doi:10.1038/cddis.2017.369

Cited by 89 publications

(78 citation statements)

References 44 publications

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“…Similarly, components of IRE1 and PERK signaling pathways may also bind to the GRP78 promoter to elevate GRP78 transcription 46,47 . The roles of PDI in the regulation of ER stress sensor proteins are not well understood, however, PDI is an essential redox-sensitive activator of PERK 48 . In unstressed condition, ERp57 keeps PDI in a reduced state.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma

Samanta

Tamura

Dubeau

et al. 2020

Sci Rep

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Epithelial ovarian cancer (EOC) is a leading cause of cancer-related mortality in the United States due to the late-stage disease at diagnosis. Overexpression of GRP78 and PDI following endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) promote growth and invasion in cancer. To identify novel prognostic biomarkers in EOC, here we determined the expression of ER stress-associated proteins (GRP78, ATF6 and PERK) and correlated with clinical outcome in EOC. Tissue microarray (TMA) samples from 415 tissues collected from three cancer centers (UM, USC, and KCCRI) were used to assess the expression levels of ER-associated proteins using immunohistochemistry (IHC). We observed that the expression levels of GRP78 (p < 0.0001), ATF6 (p < 0.0001), and PERK (p < 0.0001) were significantly increased in specimens of EOC compared to normal tissues, including in the serous subtype (p < 0.0001). Previously we reported that high expression of PDI correlated with poor patient survival in EOC. Here we showed that overexpression of GRP78 and PDI protein expression correlated with poor patient survival (p = 0.03), while low expression of combined GRP78 and PDI correlated with better survival (p = 0.01) in high-grade serous. The increased expression of ER stress-associated proteins in EOC suggests a role for ER stress and the UPR in EOC. More importantly, our results demonstrate that GRP78 and PDI are potential biomarkers for EOC and could be used as dual prognostic markers. Epithelial ovarian cancers (EOC) are a leading cause of death from gynecologic malignancies and the fifth most common cause of cancer deaths in the United States, in large part because they are typically diagnosed at late stage 1. Surgery and platinum/taxane-based chemotherapy form the mainstay of treatment 2. Despite relatively high initial response rates, the majority of patients with advanced disease unfortunately recur following first-line treatment 2,3. Previous studies showed that detection of the disease at an early stage is associated with prolonged survival, whereas patients diagnosed with advanced-stage EOC have significantly shorter survival rates 4-6. Thus, early detection is still regarded as an important, albeit elusive, criterion for successfully treating and optimizing survival for patients with EOC. The commonly used biomarker, CA-125, to detect EOC is neither sensitive nor specific enough for early detection of the disease 4. Hence, the discovery of new biomarkers is needed. The activation of the unfolded protein response (UPR) and overexpression of chaperone proteins, 78 kDa glucose-regulated protein (GRP78) and protein disulfide isomerase (PDI), following ER stress promotes growth, survival, and invasion 7-13. Cellular stress, due to the accumulation of misfolded/unfolded proteins, activates the UPR that halts the translation of proteins and stimulates the degradation of unfolded and aggregated proteins. Ultimately, the cell undergoes apoptosis unless protein homeostasis is restored 14. Thus, in the presence...

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Section: Discussionmentioning

confidence: 99%

Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma

Samanta

Tamura

Dubeau

et al. 2020

Sci Rep

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“…7C, alteration of intracellular redox state in FaO cells resulted associated to a progressive and persistent increased expression of PDI family involved in UPR triggering. Among PDI proteins, we found a progressive increase in PDI and ERp72 protein expression, and a decrease of ERp57 and calnexin 43 protein expression except for an unexpected increase at 42 and 30 hours, respectively. α-LA induces ER stress in HepG2 cells through upregulation of UPR.…”

Section: α-La-treated Fao Cells Show Dysregulation Of Genes Involved mentioning

confidence: 72%

α-Lipoic acid induces Endoplasmic Reticulum stress-mediated apoptosis in hepatoma cells

Pibiri

Sulas

Camboni

et al. 2020

Sci Rep

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Hepatocellular carcinoma (Hcc) is the most common liver cancer and a major cause of adult death. the current treatments for HCC suffer from drug resistance and poor prognosis; therefore, novel therapeutic agents are urgently needed. Phytochemicals have been proposed to treat a range of cancers. Among them, α-lipoic acid (α-LA), a naturally synthesized antioxidant found in various dietary animal and plant sources, prevents oxidant-mediated cell death in normal cells while inducing apoptosis in several cancer cell lines. Previously, we demonstrated that the treatment of hepatoma cells with α-LA induced apoptosis, which was preceded by the generation of reactive oxygen species (ROS) and activation of the p53 protein, a known inducer of mitochondria-mediated apoptosis. Several studies have shown that ROS-induced apoptosis is associated with endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) activation. Herein, we investigated if α-LA-induced apoptosis in hepatoma cell lines was ER stress-and UPR-mediated by gene expression profiling analyses. UPR and ER stress pathways were the most up-regulated after treatment with α-LA. This finding, which has been confirmed by expression analyses of ER-and UPR-associated proteins, provides a better understanding of the molecular mechanisms behind the anti-tumoral action of α-LA on hepatoma cells.

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“…PDIs are known to be responsible for the oxidation (formation), reduction (break down) and isomerization (rearrangement) of protein disulfide bonds via disulfide interchange activity. The other major role of PDIs is in general chaperone activity and recent studies have also identified PDI for its role as PERK activator (50–52). In Figure 2, it is interesting to observe that mRNA-level upregulation is countered by protein-level down-regulation of DnaJ heat shock protein family (Hsp40) member C3 (DNAJC3), which is a known inhibitor of PERK (53).…”

Section: Resultsmentioning

confidence: 99%

multiSLIDE: a web server for exploring connected elements of biological pathways in multi-omics data

Ghosh

Datta

Choi

2019

Preprint

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We present multiSLIDE, an open-source tool for query-driven visualization of quantitative single- or multiomics data. Using pathways and networks as the basis for data linkage, multiSLIDE provides an interactive platform for querying the multi-omics data by genes, pathways, and intermolecular relationships. Representing individual -omics levels as separate heatmaps, multiSLIDE visualizes quantitative data for selected genes at all omics levels in a single snapshot. The tool also provides functionalities to arrange data both ways, by their phenotypic characteristics and by their molecular interactions or co-membership to common pathways. Built-in statistical tests and clustering methods provide display subsets of interesting genes or rearrange the genes based on expression patterns. All visualization panels are fully customizable, and both the graphics and the analysis workspace can be saved and shared between collaborating parties. We demonstrate the utility of multiSLIDE through two example studies. First, with a time-course data of HeLa cells, subjected to dithiothreitol induced endoplasmic reticulum stress, we visualized different stages of unfolded protein response and identified temporal patterns of gene expression response at the mRNA and protein levels. Second, through joint visualization of mRNA and protein expression of TCGA/CPTAC Invasive Breast Carcinoma data, we explored the estrogen receptor α regulon and prioritized clusters of genes associated with PAM50 basal-like subtype.

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PDI is an essential redox-sensitive activator of PERK during the unfolded protein response (UPR)

Cited by 89 publications

References 44 publications

Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma

Clinicopathological significance of endoplasmic reticulum stress proteins in ovarian carcinoma

α-Lipoic acid induces Endoplasmic Reticulum stress-mediated apoptosis in hepatoma cells

multiSLIDE: a web server for exploring connected elements of biological pathways in multi-omics data

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