The endoplasmic reticulum stress/unfolded protein response in gliomagenesis, tumor progression and as a therapeutic target in glioblastoma

Fajardo, Natalia; Meijer, Coby; Kruyt, Frank A.E.

doi:10.1016/j.bcp.2016.04.008

Cited by 105 publications

(65 citation statements)

References 65 publications

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“…In cancers, microenvironmental conditions, like hypoxia, reactive oxygen species, and nutrient deprivation, may lead to the accumulation of unfolded or misfolded proteins and induce ER stress [2,3,4,6,7]. If the ER stress is not relieved, the tumor cells may become apoptotic.…”

Section: Discussionmentioning

confidence: 99%

“…Protein maturation requires the coordinated activity of many chaperones and folding enzymes [1,2]. When the number of unfolded proteins exceeds the capacity of the ER, cellular protein homeostasis is disrupted and ER stress occurs, leading to the accumulation of unfolded or misfolded proteins [1,2,3]. To reduce the excessive protein load, cells activate the unfolded protein response (UPR), which causes transient attenuation of protein translation, degradation of misfolded proteins, and induction of molecular chaperones and folding enzymes to augment the ER capacity for protein folding and degradation [2].…”

Section: Endoplasmic Reticulum Stress In Cancersmentioning

confidence: 99%

“…To reduce the excessive protein load, cells activate the unfolded protein response (UPR), which causes transient attenuation of protein translation, degradation of misfolded proteins, and induction of molecular chaperones and folding enzymes to augment the ER capacity for protein folding and degradation [2]. The UPR is controlled by glucose-regulated protein 78 (GRP78) and three different ER transmembrane sensor proteins: protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor-6 [1,3,4,5]. GRP78 acts on newly-synthesized proteins by chaperoning them through folding, assembly, and translocation across the ER membrane [6].…”

Section: Endoplasmic Reticulum Stress In Cancersmentioning

confidence: 99%

“…If this ER stress is not relieved, the injured cells may become apoptotic [2]. ER stress can be induced by various insults, such as hypoxia, reactive oxygen species, nutrient deprivation, disruption of calcium homeostasis, inhibition of protein glycosylation or disulfide bond formation, and viral or bacterial infection [2,3]. …”

Section: Endoplasmic Reticulum Stress In Cancersmentioning

confidence: 99%

“…ER stress also plays an important role in tumor cell survival, tumor progression, angiogenesis, metastasis, and drug resistance; common conditions in the tumor microenvironment such as hypoxia, reactive oxygen species, and nutrient deprivation can trigger the UPR [2,3,4,6,7]. Tumor cells often produce more mutant proteins than the normal ER capacity can handle because of rapid biosynthesis in cancers, and eventually the nutrient requirements exceed the capacity of the vascular supply, making the tumors hypoxic and causing tumor cell apoptosis [1,5,6].…”

Section: Endoplasmic Reticulum Stress In Cancersmentioning

confidence: 99%

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HDAC Inhibitors and RECK Modulate Endoplasmic Reticulum Stress in Tumor Cells

Chen

Tsai

Tseng

2017

IJMS

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In the tumor microenvironment hypoxia and nutrient deprived states can induce endoplasmic reticulum (ER) stress. If ER stress is not relieved, the tumor cells may become apoptotic. Therefore, targeting ER homeostasis is a potential strategy for cancer treatment. Various chemotherapeutic agents including histone deacetylase (HDAC) inhibitors can induce ER stress to cause cell death in cancers. Some HDAC inhibitors can prevent HDAC from binding to the specificity protein 1-binding site of the promoter of reversion-inducing cysteine-rich protein with Kazal motifs (RECK) and up-regulate RECK expression. Up-regulation of RECK expression by HDAC inhibitors has been observed in various cancer types. RECK is a tumor and metastasis suppressor gene and is critical for regulating tumor cell invasiveness and metastasis. RECK also modulates ER stress via binding to and sequestering glucose-regulated protein 78 protein, so that the transmembrane sensors, such as protein kinase RNA-like ER kinase are released to activate eukaryotic translational initiation factor 2α phosphorylation and enhance ER stress. Therefore, HDAC inhibitors may directly induce ER stress or indirectly induce this stress by up-regulating RECK in cancer cells.

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Section: Discussionmentioning

confidence: 99%

Section: Endoplasmic Reticulum Stress In Cancersmentioning

confidence: 99%

Section: Endoplasmic Reticulum Stress In Cancersmentioning

confidence: 99%

Section: Endoplasmic Reticulum Stress In Cancersmentioning

confidence: 99%

Section: Endoplasmic Reticulum Stress In Cancersmentioning

confidence: 99%

See 3 more Smart Citations

HDAC Inhibitors and RECK Modulate Endoplasmic Reticulum Stress in Tumor Cells

Chen

Tsai

Tseng

2017

IJMS

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Sp2 promotes invasion and metastasis of hepatocellular carcinoma by targeting TRIB3 protein

et al. 2020

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ObjectiveTo explore the biological function and molecular mechanism of Sp2 in hepatocellular carcinoma (HCC).MethodsTissue microarray immunohistochemistry and western blot were used to study the expression of Sp2 in hepatocellular tissue and adjacent non‐neoplastic tissues (ANT). In HCC cell lines, the role of Sp2 was determined by in vitro experiments such as CCK8, clone formation test, Transwell assay, wound‐healing assay, and flow cytometry apoptotic analysis, and its possible mechanism was analyzed.ResultsCompared with ANT, Sp2 expression in HCC tissues was significantly up‐regulated, which was strongly associated with stage of tumor and poor prognosis of patients. TCGA database were further confirmed these results. Besides, functional studies had shown that Sp2 knockdown not only leads to a decrease in cell proliferation and an increase in cell apoptosis but also inhibits the cells' abilities of migration and invasion. Sp2 silencing could inhibit the expression of TRIB3 protein and down‐regulate the endoplasmic reticulum stress (ERS) level of HCC.ConclusionSp2 may play a part in promoting cancer by regulating TRIB3 protein, which may be a factor of prognostic and a potential new therapeutic target for HCC.

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SEL1L plays a major role in human malignant gliomas

Mellai

Annovazzi

Boldorini

et al. 2019

The Journal of Pathology CR

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Suppressor of Lin‐12‐like (C. elegans) (SEL1L) participates in the endoplasmic reticulum‐associated protein degradation pathway, malignant transformation and stem cell biology. We explored the role of SEL1L in 110 adult gliomas, of different molecular subtype and grade, in relation to cell proliferation, stemness, glioma‐associated microglia/macrophages (GAMs), prognostic markers and clinical outcome. SEL1L protein expression was assessed by immunohistochemistry and Western blotting. Genetic and epigenetic alterations were detected by molecular genetics techniques. SEL1L was overexpressed in anaplastic gliomas (World Health Organization [WHO] grade III) and in glioblastoma (GB, WHO grade IV) with the highest labelling index (LI) in the latter. Immunoreactivity was significantly associated with histological grade (p = 0.002) and cell proliferation index Ki‐67/MIB‐1 (p = 0.0001). In GB, SEL1L co‐localised with stemness markers Nestin and Sox2. Endothelial cells and vascular pericytes of proliferative tumour blood vessels expressed SEL1L suggesting a role in tumour neo‐vasculature. GAMs consistently expressed SEL1L. SEL1L overexpression was significantly associated with TERT promoter mutations (p = 0.0001), EGFR gene amplification (p = 0.0013), LOH on 10q (p = 0.0012) but was mutually exclusive with IDH1/2 mutations (p = 0.0001). SEL1L immunoreactivity correlated with tumour progression and cell proliferation, conditioning poor patient survival and response to therapy. This study emphasises SEL1L as a potential biomarker for the most common subgroup of TERT mutant/EGFR amplified/IDH‐WT GBs.

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The endoplasmic reticulum stress/unfolded protein response in gliomagenesis, tumor progression and as a therapeutic target in glioblastoma

Cited by 105 publications

References 65 publications

HDAC Inhibitors and RECK Modulate Endoplasmic Reticulum Stress in Tumor Cells

HDAC Inhibitors and RECK Modulate Endoplasmic Reticulum Stress in Tumor Cells

Sp2 promotes invasion and metastasis of hepatocellular carcinoma by targeting TRIB3 protein

SEL1L plays a major role in human malignant gliomas

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