Endoplasmic reticulum stress: a key player in human disease

Marciniak, Stefan J.

doi:10.1111/febs.14740

Cited by 34 publications

(28 citation statements)

References 20 publications

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“…The both insulin-degrading enzyme and pitrilysin metallopeptidase 1 play an important role in the normal brain including glial cell function as well as many diseases, such as insulin resistance, type 2 diabetes, neurodegenerative disorders, and cancer. An important feature of all these diseases is endoplasmic reticulum stress, which is linked to the maintenance of cellular homeostasis and the fine balance between health and disease (Almanza et al 2019;Marciniak et al 2019). This stress is an integrator of the signal transduction pathway in both normal and pathological cells, including diabetic, Aβ-positive, and malignant cells because endoplasmic reticulum stress signaling pathways have connections with other plasma membrane receptor signaling networks and with numerous metabolic pathways (Moenner et al 2007;Auf et al 2010;Bravo et al 2013;Hetz et al 2013;Lee and Ozcan 2014;Manie et al 2014;Chevet et al 2015;Wang and Kaufman et al 2016;Doultsinos et al 2017;McMahon et al 2017).…”

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confidence: 99%

“…It is interesting to note that endoplasmic reticulum stress and hypoxia as well as glucose deprivation are very important and complementary factors for tumor growth and that ERN1 mediated stress signaling can significantly modify the effects of hypoxia and glucose deprivation on gene expressions (Minchenko et al 2014(Minchenko et al , 2015b(Minchenko et al , 2016(Minchenko et al , 20172019;Zhao et al 2017). However, the detailed molecular mechanisms of the interaction of hypoxia and glucose deprivation with ERN1 mediated stress signaling pathway are complex and requires further study.…”

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confidence: 99%

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Expression of IDE and PITRM1 genes in ERN1 knockdown U87 glioma cells: effect of hypoxia and glucose deprivation

Minchenko

Khita

Tsymbal

et al. 2020

Endocrine Regulations

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Objective. The aim of the present investigation was to study the expression of genes encoding polyfunctional proteins insulinase (insulin degrading enzyme, IDE) and pitrilysin metallopeptidase 1 (PITRM1) in U87 glioma cells in response to inhibition of endoplasmic reticulum stress signaling mediated by ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1) for evaluation of their possible significance in the control of metabolism through ERN1 signaling as well as hypoxia, glucose and glutamine deprivations.Methods. The expression level of IDE and PITRM1 genes was studied in control and ERN1 knockdown U87 glioma cells under glucose and glutamine deprivations as well as hypoxia by quantitative polymerase chain reaction.Results. It was found that the expression level of IDE and PITRM1 genes was down-regulated in ERN1 knockdown (without ERN1 protein kinase and endoribonuclease activity) glioma cells in comparison with the control glioma cells, being more significant for PITRM1 gene. We also found up-regulation of microRNA MIR7-2 and MIRLET7A2, which have specific binding sites in 3’-untranslated region of IDE and PITRM1 mRNAs, correspondingly, and can participate in posttranscriptional regulation of these mRNA expressions. Only inhibition of ERN1 endoribonuclease did not change significantly the expression of IDE and PITRM1 genes in glioma cells. The expression of IDE and PITRM1 genes is preferentially regulated by ERN1 protein kinase. We also showed that hypoxia down-regulated the expression of IDE and PITRM1 genes and that knockdown of ERN1 signaling enzyme function modified the response of these gene expressions to hypoxia. Glucose deprivation increased the expression level of IDE and PITRM1 genes, but ERN1 knockdown enhanced only the effect of glucose deprivation on PITRM1 gene expression. Glutamine deprivation did not affect the expression of IDE gene in both types of glioma cells, but up-regulated PITRM1 gene and this up-regulation was stronger in ERN1 knockdown cells.Conclusions. Results of this investigation demonstrate that ERN1 knockdown significantly decreases the expression of IDE and PITRM1 genes by ERN1 protein kinase mediated mechanism. The expression of both studied genes was sensitive to hypoxia as well as glucose deprivation and dependent on ERN1 signaling in gene-specific manner. It is possible that the level of these genes expression under hypoxia and glucose deprivation is a result of complex interaction of variable endoplasmic reticulum stress related and unrelated regulatory factors and contributed to the control of the cell metabolism.

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confidence: 99%

mentioning

confidence: 99%

Expression of IDE and PITRM1 genes in ERN1 knockdown U87 glioma cells: effect of hypoxia and glucose deprivation

Minchenko

Khita

Tsymbal

et al. 2020

Endocrine Regulations

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“…A number of cellular stress conditions including nutritional deprivation, hypoxia, alterations in protein glycosylation and disturbances of calcium flux can lead to the accumulation and aggregation of unfolded/misfolded proteins in the ER lumen inducing ER stress (unfolded protein response (UPR)) [32,33]. We first surveyed a variety of prostate cancer cell lines and HeLa cells to gauge the effects of GlcN-induced inhibition of N-glycosylation (hereafter described as deglycosylation) on EGFR, a known glycosylated protein [34].…”

Section: Glcn Induces Er Stress and Increases Cellular Dr5 Expressionmentioning

confidence: 99%

Glucosamine Enhances TRAIL-Induced Apoptosis in the Prostate Cancer Cell Line DU145

et al. 2019

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Background: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells in cancer patients. However, patients often develop TRAIL resistance; thus, agents that can sensitize cells to TRAIL therapy would be beneficial clinically. Methods: Immunoblotting, flow cytometry, confocal microscopy, qPCR and caspase 8 activity assays were used to investigate whether glucosamine (GlcN) can sensitize cancer cells to TRAIL thereby enhancing apoptosis and potentially improving clinical response. Results: GlcN sensitized DU145 cells to TRAIL-induced apoptosis but did not increase death receptor 5 (DR5) cell surface expression. Once treated, these cells responded to TRAIL-induced apoptosis through both extrinsic and intrinsic apoptotic pathways as evidenced by the cleavage of both caspases 8 and 9. The combination of GlcN and TRAIL suppressed the expression of key anti-apoptotic factors cFLIP, BCL-XL, MCL-1 and XIAP and translocated BAK to the mitochondrial outer membrane thereby facilitating cytochrome C and SMAC release. In addition to the activation of apoptotic pathways, TRAIL-mediated inflammatory responses were attenuated by GlcN pretreatment reducing nuclear NF-kB levels and the expression of downstream target genes IL-6 and IL-8. Conclusions: GlcN/TRAIL combination could be a promising strategy for treating cancers by overcoming TRAIL resistance and abrogating TRAIL-induced inflammation.

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“…The UPR increases the folding capacity of the endoplasmic reticulum, reduces translation of new proteins, and enhances the degradation of misfolded proteins. If UPR functions fail to complete, stress is prolonged, resulting in signaling for cell apoptosis (10)(11)(12). Glucose-regulated protein 78 (GRP78), a master regulator of the endoplasmic reticulum stress response, has been further characterized as a chaperone in the cytoplasm of cancer cells as well as a signaling receptor in the cell plasma membrane (13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Chemotherapy Controls Metastasis Through Stimulatory Effects on GRP78 and Its Transcription Factor CREB3L1

et al. 2020

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To achieve a cure for metastatic breast cancer, further understanding of molecular drivers of the metastatic cascade is essential. Currently, chemotherapy regimens include doxorubicin and paclitaxel which act in part by inducing the unfolded protein response (UPR). The master regulator of the UPR, glucose regulated protein 78 (GRP78), localizes on the surface of tumor cells and is associated with metastatic disease. Cyclic AMP responsive element binding protein 3-like 1 (CREB3L1), a member of the UPR, is a breast cancer metastasis suppressor that acts on cyclic AMP to promote the expression of target genes including GRP78. The aim of the present study was to evaluate the effects of chemotherapy on CREB3L1 and cell-surface GRP78 expression and its association with the development of breast cancer metastasis. For this purpose, we use breast cancer cells migration in vitro assays and an in vivo metastatic mouse model. The results showed that chemotherapy activated CREB3L1 and enhanced cell-surface GRP78 expression specifically in triple-negative breast cancer cells (TNBC), reducing their migration and metastatic potential. CREB3L1 knockout (KO) in the triple negative MDAMB231 cell line using CRISPR/Cas9 technology led to inhibition of GRP78 expression and abrogation of the CREB3L1 metastatic suppression function. Inoculation of CREB3L1-KO MDAMB231 cells into a mouse metastatic model induced a massive metastatic profile which chemotherapy failed to prevent. These findings elucidate a potential pathway to the development of a novel treatment strategy for metastatic TNBC based on modulating CREB3L1 and cell-surface GRP78 expression by chemotherapy and GRP78-targeted drugs.

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Endoplasmic reticulum stress: a key player in human disease

Cited by 34 publications

References 20 publications

Expression of IDE and PITRM1 genes in ERN1 knockdown U87 glioma cells: effect of hypoxia and glucose deprivation

Expression of IDE and PITRM1 genes in ERN1 knockdown U87 glioma cells: effect of hypoxia and glucose deprivation

Glucosamine Enhances TRAIL-Induced Apoptosis in the Prostate Cancer Cell Line DU145

Chemotherapy Controls Metastasis Through Stimulatory Effects on GRP78 and Its Transcription Factor CREB3L1

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