ArticleActa neuropathologica2014
The tumor suppressor prostate apoptosis response-4 (Par-4) is regulated by mutant IDH1 and kills glioma stem cells.
Article in Acta neuropathologica, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Antitumor Efficacy of Arylquin 1 through Dose-Dependent Cytotoxicity, Apoptosis Induction, and Synergy with Radiotherapy in Glioblastoma Models.Biomedicines · 2024Article
- Evaluation of Temozolomide and Fingolimod Treatments in Glioblastoma Preclinical Models.Cancers · 2023Article
- The regulatory mechanisms and inhibitors of isocitrate dehydrogenase 1 in cancer.Acta pharmaceutica Sinica. B · 2023Review
- Crizotinib induces Par-4 secretion from normal cells and GRP78 expression on the cancer cell surface for selective tumor growth inhibition.American journal of cancer research · 2023Article
- Tumor Suppressor Par-4 Regulates Complement Factor C3 and Obesity.Frontiers in oncology · 2022Article
- Development of a novel prostate apoptosis response-4 (Par-4) protein entity with an extended duration of action for therapeutic treatment of cancer.Protein engineering, design & selection : PEDS · 2019Article
- Modeling the diffusion of D-2-hydroxyglutarate from IDH1 mutant gliomas in the central nervous system.Neuro-oncology · 2018Article
- Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas.Journal of neuro-oncology · 2018Article
- Induction of synthetic lethality in IDH1-mutated gliomas through inhibition of Bcl-xL.Nature communications · 2017Article
- The clinical significance of isocitrate dehydrogenase 2 in esophageal squamous cell carcinoma.American journal of cancer research · 2017Article
- Mutant IDH1 and thrombosis in gliomas.Acta neuropathologica · 2016Article
- Cancer stem cells: targeting the roots of cancer, seeds of metastasis, and sources of therapy resistance.Cancer research · 2015Review
- Secretory prostate apoptosis response (Par)-4 sensitizes multicellular spheroids (MCS) of glioblastoma multiforme cells to tamoxifen-induced cell death.FEBS open bio · 2015Article
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5 authors.
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Abstract
Prostate apoptosis response-4 (Par-4) is an endogenous tumor suppressor that selectively induces apoptosis in a variety of cancers. Although it has been the subject of intensive research in other cancers, less is known about its significance in gliomas, including whether it is regulated by key driver mutations, has therapeutic potential against glioma stem cells (GSCs), and/or is a prognostic marker. We found that patient-derived gliomas with mutant isocitrate dehydrogenase 1 have markedly lower Par-4 expression (P < 0.0001), which was validated by The Cancer Genome Atlas dataset (P = 2.0 E-13). The metabolic product of mutant IDH1, D-2-hydroxyglutarate (2-HG), can suppress Par-4 transcription in vitro via inhibition of promoter activity as well as enhanced mRNA degradation, but interestingly not by direct DNA promoter hypermethylation. The Selective for Apoptosis induction in Cancer cells (SAC) domain within Par-4 is highly active against glioma cells, including orthotopic xenografts of patient-derived primary GSCs (P < 0.0001). Among high-grade gliomas that are IDH1 wild type, those that express more Par-4 have significantly longer median survival (18.4 vs. 8.0 months, P = 0.002), a finding confirmed in two external GBM cohorts. Together, these data suggest that Par-4 is a significant component of the mutant IDH1 phenotype, that the activity of 2-HG is complex and can extend beyond direct DNA hypermethylation, and that Par-4 is a promising therapeutic strategy against GSCs. Furthermore, not every effect of mutant IDH1 necessarily contributes to the overall favorable prognosis seen in such tumors; inhibition of Par-4 may be one such effect.
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