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Endoplasmic Reticulum Stress and Unfolded Protein Response 2021

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 34859

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Prof. Ireneusz Majsterek

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Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Lodz, Poland
Interests: DNA damage and repair; kinases inhibitors; Unfolded Protein Response; eye disease
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Dear Colleagues,

The endoplasmic reticulum (ER) plays a role in the maintenance of numerous aspects of cellular and organismal homeostasis by folding, modifying, and exporting nascent secretory and transmembrane proteins. Failure of the ER's adaptive capacity results in accumulation of unfolded or malfolded proteins in the ER lumen (ER stress). To avoid cellular damage, mammalian cells activate the specific signals from the ER to the cytosol or nucleus to enhance the capacity for protein folding, attenuate the synthesis of proteins, and degrade unfolded proteins. These signaling pathways are collectively known as the unfolded protein response (UPR). UPR was originally described as a system by which cells evade damage in response to acute ER perturbation. However, recent advances have revealed that UPR also regulates cell differentiation and maturation or basal cellular homeostasis. Further, ER stress has been reported to have relationships with neurodegenerative diseases, diabetes, metabolic syndromes, and cancer. Therefore, it has been attracting attention in terms of elucidating pathogenic mechanisms and developing therapeutics.

This Special Issue provides diverse aspects of ER stress and UPR in various physiological and pathological events. We invite authors to submit original research and review articles related to any research into ER stress and UPR signaling.

Prof. Ireneusz Majsterek
Guest Editor

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Keywords

ER stress
UPR signaling
Physiological ER stress
Protein folding
Unfolded proteins
ER stress sensors
ER-associated degradation
Protein quality control
ER stress-induced cell death
Protein misfolding disease

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Published Papers (10 papers)

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Research

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11 pages, 2025 KiB

Open AccessArticle

Effect of Denervation on XBP1 in Skeletal Muscle and the Neuromuscular Junction

by Lisa A. Walter, Lauren P. Blake, Yann S. Gallot, Charles J. Arends, Randall S. Sozio, Stephen M. Onifer and Kyle R. Bohnert

Int. J. Mol. Sci. 2022, 23(1), 169; https://doi.org/10.3390/ijms23010169 - 24 Dec 2021

Cited by 3 | Viewed by 3419

Abstract

Denervation of skeletal muscle is a debilitating consequence of injury of the peripheral nervous system, causing skeletal muscle to experience robust atrophy. However, the molecular mechanisms controlling the wasting of skeletal muscle due to denervation are not well understood. Here, we demonstrate that transection of the sciatic nerve in Sprague–Dawley rats induced robust skeletal muscle atrophy, with little effect on the neuromuscular junction (NMJ). Moreover, the following study indicates that all three arms of the unfolded protein response (UPR) are activated in denervated skeletal muscle. Specifically, ATF4 and ATF6 are elevated in the cytoplasm of skeletal muscle, while XBP1 is elevated in the nuclei of skeletal muscle. Moreover, XBP1 is expressed in the nuclei surrounding the NMJ. Altogether, these results endorse a potential role of the UPR and, specifically, XBP1 in the maintenance of both skeletal muscle and the NMJ following sciatic nerve transection. Further investigations into a potential therapeutic role concerning these mechanisms are needed. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2021)

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18 pages, 2870 KiB

Open AccessArticle

Expression of Human Mutant Preproinsulins Induced Unfolded Protein Response, Gadd45 Expression, JAK-STAT Activation, and Growth Inhibition in Drosophila

by Tatsuki Yamazoe, Yasuyuki Nakahara, Hiroka Katsube and Yoshihiro H. Inoue

Int. J. Mol. Sci. 2021, 22(21), 12038; https://doi.org/10.3390/ijms222112038 - 7 Nov 2021

Cited by 1 | Viewed by 2477

Abstract

Mutations in the insulin gene (INS) are frequently associated with human permanent neonatal diabetes mellitus. However, the mechanisms underlying the onset of this genetic disease is not sufficiently decoded. We induced expression of two types of human mutant INSs in Drosophila using its ectopic expression system and investigated the resultant responses in development. Expression of the wild-type preproinsulin in the insulin-producing cells (IPCs) throughout the larval stage led to a stimulation of the overall and wing growth. However, ectopic expression of human mutant preproinsulins, hINS^C96Y and hINS^{LB15YB16delinsH}, neither of which secreted from the β-cells, could not stimulate the Drosophila growth. Furthermore, neither of the mutant polypeptides induced caspase activation leading to apoptosis. Instead, they induced expression of several markers indicating the activation of unfolded protein response, such as ER stress-dependent Xbp1 mRNA splicing and ER chaperone induction. We newly found that the mutant polypeptides induced the expression of Growth arrest and DNA-damage-inducible 45 (Gadd45) in imaginal disc cells. ER stress induced by hINS^C96Y also activated the JAK-STAT signaling, involved in inflammatory responses. Collectively, we speculate that the diabetes-like growth defects appeared as a consequence of the human mutant preproinsulin expression was involved in dysfunction of the IPCs, rather than apoptosis. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2021)

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19 pages, 6092 KiB

Open AccessArticle

Increased Post-Hypoxic Oxidative Stress and Activation of the PERK Branch of the UPR in Trap1-Deficient Drosophila melanogaster Is Abrogated by Metformin

by Alma Kokott-Vuong, Jennifer Jung, Aaron T. Fehr, Nele Kirschfink, Rozina Noristani, Aaron Voigt, Arno Reich, Jörg B. Schulz, Michael Huber and Pardes Habib

Int. J. Mol. Sci. 2021, 22(21), 11586; https://doi.org/10.3390/ijms222111586 - 28 Oct 2021

Cited by 13 | Viewed by 3317

Abstract

Hypoxia is known to impair mitochondrial and endoplasmic reticulum (ER) homeostasis. Post-hypoxic perturbations of the ER proteostasis result in the accumulation of misfolded/unfolded proteins leading to the activation of the Unfolded Protein Response (UPR). Mitochondrial chaperone TNF receptor-associated protein 1 (TRAP1) is reported to preserve mitochondrial membrane potential and to impede reactive oxygen species (ROS) production thereby protecting cells from ER stress as well as oxidative stress. The first-line antidiabetic drug Metformin has been attributed a neuroprotective role after hypoxia. Interestingly, Metformin has been reported to rescue mitochondrial deficits in fibroblasts derived from a patient carrying a homozygous TRAP1 loss-of-function mutation. We sought to investigate a putative link between Metformin, TRAP1, and the UPR after hypoxia. We assessed post-hypoxic/reperfusion longevity, mortality, negative geotaxis, ROS production, metabolic activity, gene expression of antioxidant proteins, and activation of the UPR in Trap1-deficient flies. Following hypoxia, Trap1 deficiency caused higher mortality and greater impairments in negative geotaxis compared to controls. Similarly, post-hypoxic production of ROS and UPR activation was significantly higher in Trap1-deficient compared to control flies. Metformin counteracted the deleterious effects of hypoxia in Trap1-deficient flies but had no protective effect in wild-type flies. We provide evidence that TRAP1 is crucially involved in the post-hypoxic regulation of mitochondrial/ER stress and the activation of the UPR. Metformin appears to rescue Trap1-deficiency after hypoxia mitigating ROS production and downregulating the pro-apoptotic PERK (protein kinase R-like ER kinase) arm of the UPR. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2021)

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17 pages, 3391 KiB

Open AccessArticle

Induction of Endoplasmic Reticulum Stress-Mediated Apoptosis by Aminosteroid RM-581 Efficiently Blocks the Growth of PC-3 Cancer Cells and Tumors Resistant or Not to Docetaxel

by René Maltais, Jenny Roy, Martin Perreault, Sachiko Sato, Julie-Christine Lévesque and Donald Poirier

Int. J. Mol. Sci. 2021, 22(20), 11181; https://doi.org/10.3390/ijms222011181 - 17 Oct 2021

Cited by 9 | Viewed by 4100

Abstract

Aminosteroid derivative RM-581 was previously identified as an endoplasmic-reticulum (ER) stress inducer with potent in vitro and in vivo anticancer activities. We report its evaluation in androgen-independent prostate cancer (PC-3) cells. RM-581 efficiently blocks PC-3 cell proliferation with stronger activity than that of a selection of known antineoplastic agents. This later also showed a synergistic effect with docetaxel, able to block the proliferation of docetaxel-resistant PC-3 cells and, contrary to docetaxel, did not induce cell resistance. RM-581 induced an increase in the expression level of ER stress-related markers of apoptosis, potentially triggered by the presence of RM-581 in the ER of PC-3 cells. These in vitro results were then successfully translated in vivo in a PC-3 xenograft tumor model in nude mice, showing superior blockade than that of docetaxel. RM-581 was also able to stop the progression of PC-3 cells when they had become resistant to docetaxel treatment. Concomitantly, we observed a decrease in gene markers of mevalonate and fatty acid pathways, and intratumoral levels of cholesterol by 19% and fatty acids by 22%. Overall, this work demonstrates the potential of an ER stress inducer as an anticancer agent for the treatment of prostate cancers that are refractory to commonly used chemotherapy treatments. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2021)

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13 pages, 1757 KiB

Open AccessArticle

Carfilzomib Promotes the Unfolded Protein Response and Apoptosis in Cetuximab-Resistant Colorectal Cancer

by Ahmad Zulkifli, Fiona H. Tan, Zammam Areeb, Sarah F. Stuart, Juliana Gomez, Lucia Paradiso and Rodney B. Luwor

Int. J. Mol. Sci. 2021, 22(13), 7114; https://doi.org/10.3390/ijms22137114 - 1 Jul 2021

Cited by 4 | Viewed by 3231

Abstract

Cetuximab is a common treatment option for patients with wild-type K-Ras colorectal carcinoma. However, patients often display intrinsic resistance or acquire resistance to cetuximab following treatment. Here we generate two human CRC cells with acquired resistance to cetuximab that are derived from cetuximab-sensitive parental cell lines. These cetuximab-resistant cells display greater in vitro proliferation, colony formation and migration, and in vivo tumour growth compared with their parental counterparts. To evaluate potential alternative therapeutics to cetuximab-acquired-resistant cells, we tested the efficacy of 38 current FDA-approved agents against our cetuximab-acquired-resistant clones. We identified carfilzomib, a selective proteosome inhibitor to be most effective against our cell lines. Carfilzomib displayed potent antiproliferative effects, induced the unfolded protein response as determined by enhanced CHOP expression and ATF6 activity, and enhanced apoptosis as determined by enhanced caspase-3/7 activity. Overall, our results indicate a potentially novel indication for carfilzomib: that of a potential alternative agent to treat cetuximab-resistant colorectal cancer. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2021)

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13 pages, 4742 KiB

Open AccessArticle

PERK/ATF4-Dependent ZFAS1 Upregulation Is Associated with Sorafenib Resistance in Hepatocellular Carcinoma Cells

by Jiunn-Chang Lin, Pei-Ming Yang and Tsang-Pai Liu

Int. J. Mol. Sci. 2021, 22(11), 5848; https://doi.org/10.3390/ijms22115848 - 29 May 2021

Cited by 24 | Viewed by 3996

Abstract

Sorafenib, a multi-kinase inhibitor, is the first-line treatment for advanced hepatocellular carcinoma (HCC) patients. However, this drug only provides a short improvement of patients’ overall survival, and drug resistance is commonly developed. Thus, the identification of resistant factor(s) or biomarker(s) is needed to develop more efficient therapeutic strategies. Long, non-coding RNAs (lncRNAs) have recently been viewed as attractive cancer biomarkers and drive many important cancer phenotypes. A lncRNA, ZFAS1 (ZNFX1 antisense RNA 1) has been found to promote HCC metastasis. This study found that sorafenib induced ZFAS1 expression specifically in sorafenib-resistant HCC cells. Although ZFAS1 knockdown did not restore the sensitivity of HCC cells to sorafenib, its expression may act as a resistant biomarker for sorafenib therapy. Bioinformatics analysis predicted that sorafenib tended to induce pathways related to endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in sorafenib-resistant HCC cells. In vitro experimental evidence suggested that sorafenib induced protein kinase RNA-like ER kinase (PERK)/activating transcription factor 4 (ATF4)-dependent ZFAS1 expression, and sorafenib resistance could be overcome by PERK/ATF inhibitors. Therefore, PERK/ATF4/ZFAS1 signaling axis might be an attractive therapeutic and prognostic biomarker for sorafenib therapy in HCC. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2021)

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19 pages, 3445 KiB

Open AccessArticle

Induction of the Proinflammatory Chemokine Interleukin-8 Is Regulated by Integrated Stress Response and AP-1 Family Proteins Activated during Coronavirus Infection

by Qing Chun Zhu, Shumin Li, Li Xia Yuan, Rui Ai Chen, Ding Xiang Liu and To Sing Fung

Int. J. Mol. Sci. 2021, 22(11), 5646; https://doi.org/10.3390/ijms22115646 - 26 May 2021

Cited by 22 | Viewed by 3855

Abstract

Infection induces the production of proinflammatory cytokines and chemokines such as interleukin-8 (IL-8) and IL-6. Although they facilitate local antiviral immunity, their excessive release leads to life-threatening cytokine release syndrome, exemplified by the severe cases of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this study, we investigated the roles of the integrated stress response (ISR) and activator protein-1 (AP-1) family proteins in regulating coronavirus-induced IL-8 and IL-6 upregulation. The mRNA expression of IL-8 and IL-6 was significantly induced in cells infected with infectious bronchitis virus (IBV), a gammacoronavirus, and porcine epidemic diarrhea virus, an alphacoronavirus. Overexpression of a constitutively active phosphomimetic mutant of eukaryotic translation initiation factor 2α (eIF2α), chemical inhibition of its dephosphorylation, or overexpression of its upstream double-stranded RNA-dependent protein kinase (PKR) significantly enhanced IL-8 mRNA expression in IBV-infected cells. Overexpression of the AP-1 protein cJUN or its upstream kinase also increased the IBV-induced IL-8 mRNA expression, which was synergistically enhanced by overexpression of cFOS. Taken together, this study demonstrated the important regulatory roles of ISR and AP-1 proteins in IL-8 production during coronavirus infection, highlighting the complex interactions between cellular stress pathways and the innate immune response. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2021)

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19 pages, 4970 KiB

Open AccessArticle

Autophagy Induction by Trichodermic Acid Attenuates Endoplasmic Reticulum Stress-Mediated Apoptosis in Colon Cancer Cells

by Junyan Qu, Cheng Zeng, Tingting Zou, Xu Chen, Xiaolong Yang and Zhenghong Lin

Int. J. Mol. Sci. 2021, 22(11), 5566; https://doi.org/10.3390/ijms22115566 - 25 May 2021

Cited by 8 | Viewed by 3312

Abstract

Colorectal cancer (CRC) is the third leading malignant tumor in the world, which has high morbidity and mortality. In this study we found that trichodermic acid (TDA), a secondary metabolite isolated from the plant endophytic fungus Penicillium ochrochloronthe with a variety of biological and pharmacological activities, exhibited the antitumor effects on colorectal cancer cells in vitro and in vivo. Our results showed that TDA inhibited the proliferation of colon cancer cells in a dose-dependent manner. TDA induces sustained endoplasmic reticulum stress, which triggers apoptosis through IRE1α/XBP1 and PERK/ATF4/CHOP pathways. In addition, we found that TDA mediated endoplasmic reticulum stress also induces autophagy as a protective mechanism. Moreover, combined treatment of TDA with autophagy inhibitors significantly enhanced its anticancer effect. In conclusion, our results indicated that TDA can induce ER stress and autophagy mediated apoptosis, suggesting that targeting ER stress and autophagy may be an effective strategy for the treatment of CRC. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2021)

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11 pages, 1707 KiB

Open AccessArticle

Endoplasmic Reticulum Stress Contributes to Gefitinib-Induced Apoptosis in Glioma

by Cheng-Yi Chang, Ping-Ho Pan, Chih-Cheng Wu, Su-Lan Liao, Wen-Ying Chen, Yu-Hsiang Kuan, Wen-Yi Wang and Chun-Jung Chen

Int. J. Mol. Sci. 2021, 22(8), 3934; https://doi.org/10.3390/ijms22083934 - 11 Apr 2021

Cited by 22 | Viewed by 3337

Abstract

Adequate stress on the Endoplasmic Reticulum (ER) with the Unfolded Protein Response (UPR) could maintain glioma malignancy. Uncontrolled ER stress, on the other hand, predisposes an apoptosis-dominant UPR program. We studied here the proapoptotic actions of the Epidermal Growth Factor Receptor (EGFR) inhibitor gefitinib, with the focus on ER stress. The study models were human H4 and U87 glioma cell lines. We found that the glioma cell-killing effects of gefitinib involved caspase 3 apoptotic cascades. Three branches of ER stress, namely Activating Transcription Factor-6 (ATF6), Protein Kinase R (PKR)-Like ER Kinase (PERK), and Inositol-Requiring Enzyme 1 (IRE1), were activated by gefitinib, along with the elevation of intracellular free Ca²⁺, Reactive Oxygen Species (ROS), and NADPH Oxidase2/4 (NOX2/4). Specifically, elevated IRE1 phosphorylation, Tumor Necrosis Factor (TNF) Receptor-Associated Factor-2 (TRAF2) expression, Apoptosis Signal-Regulating Kinase-1 (Ask1) phosphorylation, c-Jun N-Terminal Kinase (JNK) phosphorylation, and Noxa expression appeared in gefitinib-treated glioma cells. Genetic, pharmacological, and biochemical studies further indicated an active ROS/ER stress/Ask1/JNK/Noxa axis causing the glioma apoptosis induced by gefitinib. The findings suggest that ER-stress-based therapeutic targeting could be a promising option in EGFR inhibitor glioma therapy, and may ultimately achieve a better patient response. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2021)

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Review

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14 pages, 725 KiB

Open AccessReview

The Role of ER Stress-Related Phenomena in the Biology of Malignant Peripheral Nerve Sheath Tumors

by Anna Walczak, Maciej Radek and Ireneusz Majsterek

Int. J. Mol. Sci. 2021, 22(17), 9405; https://doi.org/10.3390/ijms22179405 - 30 Aug 2021

Viewed by 2221

Abstract

Malignant peripheral nerve sheath tumors (MPNST) are rare but one of the most aggressive types of cancer. Currently, there are no effective chemotherapy strategies for these malignancies. The inactivation of the neurofibromatosis type I (NF1) gene, followed by loss of TP53, is an early stage in MPNST carcinogenesis. NF1 is a negative regulator of the Ras proteins family, which are key factors in regulating cell growth, homeostasis and survival. Cell cycle dysregulation induces a stress phenotype, such as proteotoxic stress, metabolic stress, and oxidative stress, which should result in cell death. However, in the case of neoplastic cells, we observe not only the avoidance of apoptosis, but also the impact of stress factors on the treatment effectiveness. This review focuses on the pathomechanisms underlying MPNST cells physiology, and discusses the possible ways to develop a successful treatment based on the molecular background of the disease. Full article

(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2021)

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