bims-unfpre Biomed News
on Unfolded protein response
Issue of 2023‒10‒15
fifteen papers selected by
Susan Logue, University of Manitoba
  1. GRP78 inhibitor HA15 increases the effect of Bortezomib on eradicating multiple myeloma cells through triggering endoplasmic reticulum stress.
  2. CXCR3 antagonist rescues ER stress and reduces inflammation and JEV infection in mice brain.
  3. Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.
  4. Dual roles of UPRer and UPRmt in neurodegenerative diseases.
  5. Targeting endoplasmic reticulum stress signaling in ovarian cancer therapy.
  6. Reversion of chemoresistance by endocannabinoid-induced ER stress and autophagy activation in ovarian cancer.
  7. Increased Ca2 + transport across the mitochondria-associated membranes by Mfn2 inhibiting endoplasmic reticulum stress in ischemia/reperfusion kidney injury.
  8. Combination therapy with HSP90 inhibitors and piperlongumine promotes ROS-mediated ER stress in colon cancer cells.
  9. Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress.
  10. Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion.
  11. Glial-derived mitochondrial signals affect neuronal proteostasis and aging.
  12. LW-213 induces immunogenic tumor cell death via ER stress mediated by lysosomal TRPML1.
  13. Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis.
  14. NRF3 suppresses squamous carcinogenesis, involving the unfolded protein response regulator HSPA5.
  15. EDEM1 regulates the insulin mRNA level by inhibiting the endoplasmic reticulum stress-induced IRE1/JNK/c-Jun pathway.
  1. Heliyon. 2023 Sep;9(9): e19806
    GRP78 inhibitor HA15 increases the effect of Bortezomib on eradicating multiple myeloma cells through triggering endoplasmic reticulum stress.
    Yirong Chen, Yuchen Tao, Kexin Hu, Jiahui Lu.
      Bortezomib (BTZ), a selective proteasome inhibitor, exhibits a significant efficacy in the therapy of multiple myeloma (MM) partly through triggering endoplasmic reticulum (ER) stress-dependent apoptosis. However, sensitivity to BTZ varies greatly among patients. ER stress functions as a double-edged sword in regulating cell survival depending on cell context and ER stress extent. The major aim of this study was to investigate whether GRP78 inhibitor, HA15, increased the therapeutic effect of BTZ on MM to through further increasing ER stress and shifting the balance towards cell apoptosis. The biological role of BTZ and HA15 was assessed using Cell counting kit- (CCK-) 8, colony formation, and Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labelling (TUNEL) assay. We found that BTZ combined with HA15 remarkably decreased MM cell viability more effective than BTZ monotherapy, though low dose of HA15 did not exhibit a significant cytotoxicity to MM cells. BTZ combined with HA15 also repressed colony formation ability of MM cell and accelerated MM cell apoptosis compared with BTZ monotherapy. Mechanistically, HA15 synergized with BTZ to trigger ER stress, as evidence by significantly increased expression of ER stress markers (GRP78, ATF4, CHOP, and XBP1). Importantly, unfolded protein response (UPR) inhibitor significantly damaged the effect of BTZ combined with HA15 on accelerating MM cell death. In vivo, combination treatment with BTZ and HA15 inhibited tumor growth more effective than BTZ alone, whereas these effects were blocked by UPR inhibitor. Taken together, these results demonstrate that ER stress is a critical pathway in regulating MM cell survival, and that combination treatment with BTZ and HA15 may be an effective strategy to treat MM patients that fail to respond to BTZ monotherapy.
    Keywords:  Bortezomib; ER stress; GRP78; HA15; Multiple myeloma
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e19806
  2. Cytokine. 2023 Oct 07. pii: S1043-4666(23)00258-2. [Epub ahead of print]172 156380
    CXCR3 antagonist rescues ER stress and reduces inflammation and JEV infection in mice brain.
    Anamika Singh, Riya Ghosh, Prasenjit Guchhait.
      The endoplasmic reticulum (ER) is crucial for maintaining cellular homeostasis, and synthesis and folding of proteins and lipids. The ER is sensitive to stresses including viral infection that perturb the intracellular energy level and redox state, and accumulating unfolded/misfolded proteins. Viruses including Japanese encephalitis virus (JEV) activates unfolded protein response (UPR) causing ER stress in host immune cells and promotes inflammation and apoptotic cell death. The chemokine receptor CXCR3 has been reported to play important role in the accumulation of inflammatory immune cells and neuronal cell death in several disease conditions. Recently we described the involvement of CXCR3 in regulating inflammation and JEV infection in mice brain. Supplementation with a CXCR3 antagonist AMG487 significantly reduced JEV infection in the mice brain in conjunction with the downregulation of UPR pathway via PERK:eIF2α:CHOP, and decreased mitochondrial ROS generation, inflammation and apoptotic cell death. Alongside, AMG487 treatment improved interferon (IFN)-α/β synthesis in JEV-infected mice brain. Thus, suggesting a potential therapeutic role of CXCR3 antagonist against JEV infection.
    Keywords:  CXCR3 antagonist; ER stress; Inflammation; JEV infection; Mice
    DOI:  https://doi.org/10.1016/j.cyto.2023.156380
  3. EMBO Rep. 2023 Oct 11. e57228
    Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.
    Conor T Ronayne, Thomas D Jackson, Christopher F Bennett, Elizabeth A Perry, Noa Kantorovic, Pere Puigserver.
      Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations is redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline-induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α-mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases.
    Keywords:  IRE1α; MALSU1; mitochondrial disease; mitoribosome; tetracyclines
    DOI:  https://doi.org/10.15252/embr.202357228
  4. J Mol Med (Berl). 2023 Oct 10.
    Dual roles of UPRer and UPRmt in neurodegenerative diseases.
    Si Xu, Haihui Liu, Chen Wang, Yu Deng, Bin Xu, Tianyao Yang, Wei Liu.
      The unfolded protein response (UPR) is a cellular stress response mechanism induced by the accumulation of unfolded or misfolded proteins. Within the endoplasmic reticulum and mitochondria, a dynamic balance exists between protein folding mechanisms and unfolded protein levels under normal conditions. Disruption of this balance or an accumulation of unfolded proteins in these organelles can result in stress responses and UPR. The UPR restores organelle homeostasis and promotes cell survival by increasing the expression of chaperone proteins, regulating protein quality control systems, and enhancing the protein degradation pathway. However, prolonged or abnormal UPR can also have negative effects, including cell death. Therefore, many diseases, especially neurodegenerative diseases, are associated with UPR dysfunction. Neurodegenerative diseases are characterized by misfolded proteins accumulating and aggregating, and neuronal cells are particularly sensitive to misfolded proteins and are prone to degeneration. Many studies have shown that the UPR plays an important role in the pathogenesis of neurodegenerative diseases. Here, we will discuss the possible contributions of the endoplasmic reticulum unfolded protein response (UPRer) and the mitochondrial unfolded protein response (UPRmt) in the development of several neurodegenerative diseases.
    Keywords:  Endoplasmic reticulum; Mitochondrion; Neurodegenerative diseases; Unfolded protein responses
    DOI:  https://doi.org/10.1007/s00109-023-02382-9
  5. Cancer Biol Med. 2023 Oct 10. pii: j.issn.2095-3941.2023.0232. [Epub ahead of print]
    Targeting endoplasmic reticulum stress signaling in ovarian cancer therapy.
    Tianqing Yan, Xiaolu Ma, Lin Guo, Renquan Lu.
      The endoplasmic reticulum (ER), an organelle present in various eukaryotic cells, is responsible for intracellular protein synthesis, post-translational modification, and folding and transport, as well as the regulation of lipid and steroid metabolism and Ca2+ homeostasis. Hypoxia, nutrient deficiency, and a low pH tumor microenvironment lead to the accumulation of misfolded or unfolded proteins in the ER, thus activating ER stress (ERS) and the unfolded protein response, and resulting in either restoration of cellular homeostasis or cell death. ERS plays a crucial role in cancer oncogenesis, progression, and response to therapies. This article reviews current studies relating ERS to ovarian cancer, the most lethal gynecologic malignancy among women globally, and discusses pharmacological agents and possible targets for therapeutic intervention.
    Keywords:  Endoplasmic reticulum stress; ovarian cancer; targeted therapy; unfolded protein response
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2023.0232
  6. Am J Cancer Res. 2023 ;13(9): 4163-4178
    Reversion of chemoresistance by endocannabinoid-induced ER stress and autophagy activation in ovarian cancer.
    Yu-Shan Lin, Wen-Hou Huang, Keng-Fu Hsu, Ming-Jer Tang, Wen-Tai Chiu.
      The difficulty of detection at an early stage and the ease of developing resistance to chemotherapy render ovarian cancer (OVC) difficult to cure. Although several novel cancer therapies have been developed recently, drug resistance remains a concern since chemotherapy remains as the most commonly used treatment for cancer patients. Therefore, there is an urgent need to reclaim potential combination treatments for OVC. So far, there have been several research targeting the endocannabinoid system (ECS) in cancer. Among the various cannabinoid-based drugs, endocannabinoids, which are lipid molecules generated in the body, have been reported to produce many anti-tumor effects; however, research investigating the anti-chemoresistance effect of endocannabinoids in OVC remains unclear. In this study, we aimed to combine endocannabinoids, anandamide (AEA), and 2-arachidonoylglycerol (2-AG) with chemotherapeutic drugs as a combination approach to treat OVC. Our results showed that OVC cells expressed both cannabinoid receptors (CBR), CB1 and CB2, suggesting the possibility of endocannabinoid system (ECS) as a target. We found that the anti-chemoresistance effect mediated by endocannabinoids was caused by upregulation of ceramide levels, leading to severe endoplasmic reticulum (ER) stress and increased autophagy in chemoresistant cancer cells. Therefore, chemoresistant cancer cell growth was inhibited, and cell apoptosis was induced under combined treatments. Based on our results, endocannabinoids overcomed chemoresistance of OVC cells in vitro. Our findings suggest that drugs targeting ECS may have the potential to be adjuvants for chemotherapy by increasing the efficacy of chemotherapeutic drugs and decreasing their side effects.
    Keywords:  ER stress; Ovarian cancer; autophagy; chemoresistance; endocannabinoid system
  7. Sci Rep. 2023 Oct 12. 13(1): 17257
    Increased Ca2 + transport across the mitochondria-associated membranes by Mfn2 inhibiting endoplasmic reticulum stress in ischemia/reperfusion kidney injury.
    Shun Wang, Xiaohong Sang, Suhua Li, Wenjun Yang, Shihan Wang, Haixia Chen, Chen Lu.
      Renal ischemia/reperfusion (I/R) injury, which leads to acute kidney injury (AKI), is a major cause of morbidity and mortality in a variety of clinical situations. This study aimed to investigate the protective role of Mfn2 during renal I/R injury. Overexpression of Mfn2 in NRK-52E rat renal tubular epithelial cells and rats, then we constructed hypoxia reoxygenation (H/R) cells and I/R rat model. Apoptosis, ROS, ATP, Ca2+ levels in cells and rats, as well as renal tissue and functional injury in rats were detected respectively. Endoplasmic reticulum (ER) stress was further examined in cells and rats. The morphological changes of mitochondria-associated ER membranes (MAMs) were also detected. Mfn2 expression is reduced in H/R-treated NRK-52E cells and renal tissue of I/R rats. At the cellular level, overexpression of Mfn2 promoted cell proliferation, inhibited cell apoptosis, attenuated mitochondrial damage and Ca2+ overload, and ER stress. In addition, Mfn2 also restored the MAMs structure. In vivo experiments found that overexpression of Mfn2 could improve renal function and alleviate tissue injury. Concomitant with elevated Mfn2 expression in the kidney, reduced renal cell apoptosis, restored mitochondrial function, and reduced calcium overload. Finally, ER stress in rat kidney tissue was alleviated after overexpression of Mfn2. These results reveal that Mfn2 contributes to ER stress, mitochondrial function, and cell death in I/R injury, which provides a novel therapeutic target for AKI.
    DOI:  https://doi.org/10.1038/s41598-023-44538-0
  8. Cell Death Discov. 2023 Oct 13. 9(1): 375
    Combination therapy with HSP90 inhibitors and piperlongumine promotes ROS-mediated ER stress in colon cancer cells.
    Chenyu Qiu, Xin Shen, Hui Lu, Yinghua Chen, Chenxin Xu, Peisen Zheng, Yiqun Xia, Junqi Wang, Yafei Zhang, Shaotang Li, Peng Zou, Ri Cui, Jundixia Chen.
      Colon cancer is a major cause of cancer-related death. Despite recent improvements in the treatment of colon cancer, new strategies to improve the overall survival of patients are urgently needed. Heat shock protein 90 (HSP90) is widely recognized as a promising target for treating various cancers, including colon cancer. However, no HSP90 inhibitor has been approved for clinical use due to limited efficacy. In this study, we evaluated the antitumor activities of HSP90 inhibitors in combination with piperlongumine in colon cancer cells. We show that combination treatment with HSP90 inhibitors and piperlongumine displayed strong synergistic interaction in colon cancer cells. These agents synergize by promoting ER stress, JNK activation, and DNA damage. This process is fueled by oxidative stress, which is caused by the accumulation of reactive oxygen species. These studies nominated piperlongumine as a promising agent for HSP90 inhibitor-based combination therapy against colon cancer.
    DOI:  https://doi.org/10.1038/s41420-023-01672-y
  9. Biomed Pharmacother. 2023 Oct 10. pii: S0753-3322(23)01465-8. [Epub ahead of print]168 115667
    Soluble epoxide hydrolase-targeting PROTAC activates AMPK and inhibits endoplasmic reticulum stress.
    Mona Peyman, Emma Barroso, Andreea L Turcu, Francesc Estrany, Dáire Smith, Javier Jurado-Aguilar, Patricia Rada, Christophe Morisseau, Bruce D Hammock, Ángela M Valverde, Xavier Palomer, Carles Galdeano, Santiago Vázquez, Manuel Vázquez-Carrera.
      Soluble epoxide hydrolase (sEH) is a drug target with the potential for therapeutic utility in the areas of inflammation, neurodegenerative disease, chronic pain, and diabetes, among others. Proteolysis-targeting chimeras (PROTACs) molecules offer new opportunities for targeting sEH, due to its capacity to induce its degradation. Here, we describe that the new ALT-PG2, a PROTAC that degrades sEH protein in the human hepatic Huh-7 cell line, in isolated mouse primary hepatocytes, and in the liver of mice. Remarkably, sEH degradation caused by ALT-PG2 was accompanied by an increase in the phosphorylated levels of AMP-activated protein kinase (AMPK), while phosphorylated extracellular-signal-regulated kinase 1/2 (ERK1/2) was reduced. Consistent with the key role of these kinases on endoplasmic reticulum (ER) stress, ALT-PG2 attenuated the levels of ER stress and inflammatory markers. Overall, the findings of this study indicate that targeting sEH with degraders is a promising pharmacological strategy to promote AMPK activation and to reduce ER stress and inflammation.
    Keywords:  AMPK; ER stress; Hepatocyte; PROTAC; SEH
    DOI:  https://doi.org/10.1016/j.biopha.2023.115667
  10. bioRxiv. 2023 Sep 29. pii: 2023.09.29.560203. [Epub ahead of print]
    Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion.
    Abigael Cheruiyot, Jennifer Hollister-Lock, Brooke Sullivan, Hui Pan, Jonathan M Dreyfuss, Susan Bonner-Weir, Jean E Schaffer.
      Pancreatic β-cells are specialized for coupling glucose metabolism to insulin peptide production and secretion. Acute glucose exposure robustly and coordinately increases translation of proinsulin and proteins required for secretion of mature insulin peptide. By contrast, chronically elevated glucose levels that occur during diabetes impair β-cell insulin secretion and have been shown experimentally to suppress insulin translation. Whether translation of other genes critical for insulin secretion are similarly downregulated by chronic high glucose is unknown. Here, we used high-throughput ribosome profiling and nascent proteomics in MIN6 insulinoma cells to elucidate the genome-wide impact of sustained high glucose on β-cell mRNA translation. Prior to induction of ER stress or suppression of global translation, sustained high glucose suppressed glucose-stimulated insulin secretion and downregulated translation of not only insulin, but also of mRNAs related to insulin secretory granule formation, exocytosis, and metabolism-coupled insulin secretion. Translation of these mRNAs was also downregulated in primary rat and human islets following ex-vivo incubation with sustained high glucose and in an in vivo model of chronic mild hyperglycemia. Furthermore, translational downregulation decreased cellular abundance of these proteins. Our findings uncover a translational regulatory circuit during β-cell glucose toxicity that impairs expression of proteins with critical roles in β-cell function.
    DOI:  https://doi.org/10.1101/2023.09.29.560203
  11. Sci Adv. 2023 Oct 13. 9(41): eadi1411
    Glial-derived mitochondrial signals affect neuronal proteostasis and aging.
    Raz Bar-Ziv, Naibedya Dutta, Adam Hruby, Edward Sukarto, Maxim Averbukh, Athena Alcala, Hope R Henderson, Jenni Durieux, Sarah U Tronnes, Qazi Ahmad, Theodore Bolas, Joel Perez, Julian G Dishart, Matthew Vega, Gilberto Garcia, Ryo Higuchi-Sanabria, Andrew Dillin.
      The nervous system plays a critical role in maintaining whole-organism homeostasis; neurons experiencing mitochondrial stress can coordinate the induction of protective cellular pathways, such as the mitochondrial unfolded protein response (UPRMT), between tissues. However, these studies largely ignored nonneuronal cells of the nervous system. Here, we found that UPRMT activation in four astrocyte-like glial cells in the nematode, Caenorhabditis elegans, can promote protein homeostasis by alleviating protein aggregation in neurons. Unexpectedly, we find that glial cells use small clear vesicles (SCVs) to signal to neurons, which then relay the signal to the periphery using dense-core vesicles (DCVs). This work underlines the importance of glia in establishing and regulating protein homeostasis within the nervous system, which can then affect neuron-mediated effects in organismal homeostasis and longevity.
    DOI:  https://doi.org/10.1126/sciadv.adi1411
  12. Cancer Lett. 2023 Oct 06. pii: S0304-3835(23)00386-5. [Epub ahead of print]577 216435
    LW-213 induces immunogenic tumor cell death via ER stress mediated by lysosomal TRPML1.
    Meng-Yuan Zhu, Ting Wang, Hai-di Wang, Hong-Zheng Wang, Hong-Yu Chen, Shuai Zhang, Yong-Jian Guo, Hui Li, Hui Hui.
      Dying tumor cells release biological signals that exhibit antigenicity, activate cytotoxic T lymphocytes, and induce immunogenic cell death (ICD), playing a key role in immune surveillance. We demonstrate that the flavonoid LW-213 activates endoplasmic reticulum stress (ERS) in different tumor cells and that the lysosomal calcium channel TRPML1 mediates the ERS process in human cellular lymphoma Hut-102 cells. Apoptotic tumor cells induced by ERS often possess immunogenicity. Tumor cells treated with LW-213 exhibit damage-associated molecular patterns (DAMPs), including calreticulin translocation to the plasma membrane and extracellular release of ATP and HMGB1. When co-cultured with antigen-presenting cells (APCs), LW-213-treated tumor cells activated APCs. Two groups of C57BL/6J mice were inoculated with Lewis cells: a "vaccine group", which demonstrated that LW-213-treated tumor cells promote the maturation of dendritic cells and increase CD8+ T cells infiltration in the tumor microenvironment and a "pharmacodynamic group", treated with a combination of LW-213 and PD1/PD-L1 inhibitor (BMS-1), which reduced tumor growth and significantly prolonged the survival time of mice in the "pharmacodynamic group". Therefore, LW-213 can be developed as a novel ICD inducer, providing a new concept for antitumor immunotherapy.
    Keywords:  Calcium signaling; DC; Damage associated molecular patterns (DAMPs); Immunotherapy; Lysosome; PD1/PD-L1
    DOI:  https://doi.org/10.1016/j.canlet.2023.216435
  13. Nat Commun. 2023 Oct 12. 14(1): 6414
    Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis.
    Mattheus H E Wildschut, Julien Mena, Cyril Dördelmann, Marc van Oostrum, Benjamin D Hale, Jens Settelmeier, Yasmin Festl, Veronika Lysenko, Patrick M Schürch, Alexander Ring, Yannik Severin, Michael S Bader, Patrick G A Pedrioli, Sandra Goetze, Audrey van Drogen, Stefan Balabanov, Radek C Skoda, Massimo Lopes, Bernd Wollscheid, Alexandre P A Theocharides, Berend Snijder.
      Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either JAK2 or Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment.
    DOI:  https://doi.org/10.1038/s41467-023-42101-z
  14. EMBO Mol Med. 2023 Oct 09. e17761
    NRF3 suppresses squamous carcinogenesis, involving the unfolded protein response regulator HSPA5.
    Selina Gurri, Beat Siegenthaler, Michael Cangkrama, Gaetana Restivo, Marcel Huber, James Saliba, Reinhard Dummer, Volker Blank, Daniel Hohl, Sabine Werner.
      Epithelial skin cancers are extremely common, but the mechanisms underlying their malignant progression are still poorly defined. Here, we identify the NRF3 transcription factor as a tumor suppressor in the skin. NRF3 protein expression is strongly downregulated or even absent in invasively growing cancer cells of patients with basal and squamous cell carcinomas (BCC and SCC). NRF3 deficiency promoted malignant conversion of chemically induced skin tumors in immunocompetent mice, clonogenic growth and migration of human SCC cells, their invasiveness in 3D cultures, and xenograft tumor formation. Mechanistically, the tumor-suppressive effect of NRF3 involves HSPA5, a key regulator of the unfolded protein response, which we identified as a potential NRF3 interactor. HSPA5 levels increased in the absence of NRF3, thereby promoting cancer cell survival and migration. Pharmacological inhibition or knock-down of HSPA5 rescued the malignant features of NRF3-deficient SCC cells in vitro and in preclinical mouse models. Together with the strong expression of HSPA5 in NRF3-deficient cancer cells of SCC patients, these results suggest HSPA5 inhibition as a treatment strategy for these malignancies in stratified cancer patients.
    Keywords:  HSPA5; NRF3; malignancy; skin carcinogenesis; unfolded protein response
    DOI:  https://doi.org/10.15252/emmm.202317761
  15. iScience. 2023 Oct 20. 26(10): 107956
    EDEM1 regulates the insulin mRNA level by inhibiting the endoplasmic reticulum stress-induced IRE1/JNK/c-Jun pathway.
    Petruta R Flintoaca Alexandru, Gabriela N Chiritoiu, Daniela Lixandru, Sabina Zurac, Constantin Ionescu-Targoviste, Stefana M Petrescu.
      Pancreatic beta cells produce and secrete insulin as a response to rises in blood glucose. Despite the advances in understanding glucose-regulated insulin transcription and translation the mechanisms triggering the synthesis of new insulin molecules are still incompletely described. In this report, we identify EDEM1 as a new modulator of insulin synthesis and secretion. In the presence of EDEM1, INS-1E cells secrete significantly more insulin upon glucose stimulation compared to control cells. We found that overexpression of EDEM1 inhibited the IRE1/JNK/c-Jun pathway, leading to an increase in the insulin mRNA level. Similarly, EDEM1 transduced human islets secreted significantly more insulin upon stimulation. Furthermore, EDEM1 improved insulin secretion restoring normoglycemia and glucose tolerance in diabetic rats. We propose EDEM1 as a regulator of the UPR via IRE1/XBP1s and IRE1/JNK/c-Jun signaling cascades and insulin transcription in pancreatic β-cells, supporting EDEM1 as a potential target for the treatment of diabetes.
    Keywords:  Biochemistry; Cell biology; Molecular biology; Physiology
    DOI:  https://doi.org/10.1016/j.isci.2023.107956
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