ArticleCell death & disease2019
ER stress and UPR activation in glioblastoma: identification of a noncanonical PERK mechanism regulating GBM stem cells through SOX2 modulation.
Article in Cell death & disease, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers, 1 of them a synthesis that pooled it.
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Who cites it
51 citing papers in PubMed, 1 synthesis or guideline pooled it, 95 citations in OpenAlex.
- Endoplasmic Reticulum Stress in Spinal Cord Injury: Pathological Roles, Molecular Targets, and Emerging Treatments: A Systematic Review.Molecular neurobiology · 2026Pooled it
- Mitochondrial Metabolic Reprogramming in Glioma: Mechanisms of Tumorigenesis and Implications for Clinical Therapy.CNS neuroscience & therapeutics · 2026Review
- Proteomic Analysis Identifies ATE1-Dependent Arginylation Dysregulation across Meningioma Grades.Journal of proteome research · 2026Article
- Lipid metabolism as a marker for glioma aggressiveness.Bioscience reports · 2026Article
- Endoplasmic reticulum stress in brain metastatic cascade.NPJ precision oncology · 2026Review
- Unfolded Protein Response in Glioblastoma: Mechanisms of Proteostasis, Tumor Adaptation, and Therapeutic Relevance.Neurochemical research · 2026Review
- HOOK2 downregulation compromises the tumorigenic and stemness properties of ovarian cancer cells by increasing endoplasmic reticulum stress.Cell death & disease · 2026Article
- ABCG2-autophagy regulatory axis in cancer stem cells: implication in cancer metastasis, recurrence and chemotherapy resistance.Cell communication and signaling : CCS · 2026Review
- Pan-cancer analysis reveals differential PERK expression across tumour types and its potential as a therapeutic target.Discover oncology · 2026Article
- Artemisinin synergizes with CCCP in autophagic cell death induction via ER stress in uveal melanoma.iScience · 2025Article
- Signalling pathways and cellular functions of KDEL receptors: implications in cancer biology.Cellular and molecular life sciences : CMLS · 2025Review
- Modulation of Endoplasmic Reticulum Stress in Experimental Anti-Cancer Therapy.International journal of molecular sciences · 2025Review
- Review
- Multifaceted roles of UFMylation in health and disease.Acta pharmacologica Sinica · 2025Review
- Construction of an Extracellular Matrix-Related Risk Model to Analyze the Correlation Between Glioblastoma and Tumor Immunity.BioMed research international · 2025Article
- The unfolded protein response sensor PERK mediates mechanical stress-induced maturation of focal adhesion complexes in glioblastoma cells.FEBS letters · 2024Article
- The link between amyloid β and ferroptosis pathway in Alzheimer's disease progression.Cell death & disease · 2024Article
- The Proteasome Inhibitor Marizomib Evokes Endoplasmic Reticulum Stress and Promotes Apoptosis in Human Glioblastoma Cells.Pharmaceuticals (Basel, Switzerland) · 2024Article
- The unfolded protein response machinery in glioblastoma genesis, chemoresistance and as a druggable target.CNS neuroscience & therapeutics · 2024Review
- Protein homeostasis maintained by HOOK1 levels promotes the tumorigenic and stemness properties of ovarian cancer cells through reticulum stress and autophagy.Journal of experimental & clinical cancer research : CR · 2024Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Patients with aggressive brain tumors, named glioblastoma multiforme (GBM), have a poor prognoses. Here we explored if the ER stress/unfolded protein response (UPR) is involved in the pathophysiology of GBM and may provide novel therapeutic targets. Immunohistochemical analyses of a tissue microarray containing primary GBM specimens showed strong variability in expression of the UPR markers GRP78/BiP, XBP1, and ATF4. Interestingly, high ATF4 expression was associated with poor overall survival suggesting involvement of PERK signaling in GBM progression. In vitro experiments using patient-derived neurospheres, enriched for GBM stem cells (GSCs), showed high sensitivity for the ER stressor thapsigargin (Tg) mainly via PERK signaling. In contrast, neurospheres-derived differentiated GBM cells were less sensitive likely due to lower UPR activity as indicated by comparative transcriptional profiling. Tg and Tunicamycin strongly reduced neurosphere forming ability of GSCs that was linked with potent PERK-dependent downregulation of SOX2 protein. Interestingly, SOX2 downregulation occurred directly via PERK, not requiring downstream activation of the PERK-UPR pathway. Moreover, PERK inactivation resulted in aberrant serum-induced differentiation of GBM neurospheres accompanied by persistent SOX2 expression, delayed upregulation of GFAP and reduced cell adherence. In conclusion, we provide evidence that PERK signaling contributes to the prognoses of primary GBM patients and identified PERK as a novel regulator of SOX2 expression and GSC differentiation. The role of PERK appeared to be pleiotropic involving UPR-dependent, as well as novel identified noncanonical mechanisms regulating SOX2. ER stress and PERK modulation appear to provide promising therapeutic targets for therapy in GBM.
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