The tumor suppressor prostate apoptosis response-4 (Par-4) is regulated by mutant IDH1 and kills glioma stem cells

Liu, Yinxing; Gilbert, Misty R.; Kyprianou, Natasha; Rangnekar, Vivek M.; Horbinski, Craig

doi:10.1007/s00401-014-1334-7

Cited by 17 publications

(16 citation statements)

References 57 publications

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“…We next investigated whether IDH1 R132H overexpression in human glioma cells altered Fn14 levels using U138 and LN18 cells engineered to overexpress this protein [33]. Control, vector-transfected cells and the IDH1 R132H cells were grown under similar conditions, harvested and Fn14 expression was assayed by Western blot analysis.…”

Section: Resultsmentioning

confidence: 99%

“…Cells were harvested and Fn14 expression was assayed by Western blot analysis. We also blotted for prostate apoptosis response-4 (PAR-4) expression as a positive control for a protein regulated by IDH1 R132H activity [33]. Drug treatment led to a transient increase in Fn14 levels, with the maximal increase in Fn14 expression (~ 2.2-fold) detected after 2 days of drug treatment (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…U138 and LN18 human glioma cell lines stably transfected with either vector or IDH1 R132H plasmid DNA [33] were obtained from Dr. Craig Horbinski (Northwestern University, Evanston, IL) and grown at 37 °C in a humidified incubator (95% air, 5% CO 2 ) in DMEM supplemented with 10% fetal bovine serum and 1% penicillin–streptomycin (1000 units/l). For the AGI-5198 treatment experiment, LN18 IDH1 R132H cells were either treated with vehicle (DMSO) or AGI-5198 (1 μM; MedChem Express; Monmouth Junction, NJ) for 1, 2 or 3 days.…”

Section: Methodsmentioning

confidence: 99%

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Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

et al. 2018

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The TNF receptor superfamily member Fn14 is overexpressed by many solid tumor types, including glioblastoma (GBM), the most common and lethal form of adult brain cancer. GBM is notable for a highly infiltrative growth pattern and several groups have reported that high Fn14 expression levels can increase tumor cell invasiveness. We reported previously that the mesenchymal and proneural GBM transcriptomic subtypes expressed the highest and lowest levels of Fn14 mRNA, respectively. Given the recent histopathological re-classification of human gliomas by the World Health Organization based on isocitrate dehydrogenase 1 (IDH1) gene mutation status, we extended this work by comparing Fn14 gene expression in IDH1 wild-type (WT) and mutant (R132H) gliomas and in cell lines engineered to overexpress the IDH1 R132H enzyme. We found that both low-grade and high-grade (i.e., GBM) IDH1 R132H gliomas exhibit low Fn14 mRNA and protein levels compared to IDH1 WT gliomas. Forced overexpression of the IDH1 R132H protein in glioma cells reduced Fn14 expression, while treatment of IDH1 R132H-overexpressing cells with the IDH1 R132H inhibitor AGI-5198 or the DNA demethylating agent 5-aza-2′-deoxycytidine increased Fn14 expression. These results support a role for Fn14 in the more aggressive and invasive phenotype associated with IDH1 WT tumors and indicate that the low levels of Fn14 gene expression noted in IDH1 R132H mutant gliomas may be due to epigenetic regulation via changes in DNA methylation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

et al. 2018

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“…For the prospective NMH cohort, coagulation history was also determined by chart review, with an average length of follow-up of 3.5 months (median=3.9 months, range=0.3–6.7 months), and an average time from surgery to first VTE of 0.71 months (median=0.45 months). The glioma tissue microarray (TMA) cohort containing 95 grade II-IV gliomas has been previously described [28]. Institutional Research Board approval was obtained at UK, NYU, and NMH prior to study initiation.…”

Section: Methodsmentioning

confidence: 99%

Mutant IDH1 and thrombosis in gliomas

Unruh¹,

et al. 2016

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Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for Tissue Factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26–30% of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0%). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85–90% in wild-type versus 2–6% in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.

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“…In glioblastoma multiforme (GBM), Dr. Antonio Iavarone (Columbia University, New York, NY, USA) identified novel oncogenic tyrosine kinase fusion proteins (FGFR-TACC3) as genetic drivers and targets of CSCs (17), in addition to the epigenetic regulation by transcriptional factors such as STAT3 and C/EBPβ. In short talks, Dr. Jennifer Yu (Cleveland Clinic, Cleveland, OH, USA) showed the semaphorin family member SEMA3C as a glioma stem cell-specific target, and Dr. Craig Horbinski (University of Kentucky, Lexington, KY, USA) reported on the role of proapoptotic prostate apoptosis response 4 (PAR4) in glioma stem cells (GSCs) (18). …”

Section: Genetics Epigenetics and Rna Regulators Of Cscsmentioning

confidence: 99%

Cancer Stem Cells: Targeting the Roots of Cancer, Seeds of Metastasis, and Sources of Therapy Resistance

et al. 2015

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With the goal to remove the roots of cancer, eliminate metastatic seeds, and overcome therapy resistance, the 2014 inaugural International Cancer Stem Cell (CSC) Conference at Cleveland, OH, convened together over 320 investigators, including 55 invited world-class speakers, 25 short oral presenters, and 100 poster presenters, to gain an in-depth understanding of CSCs and explore therapeutic opportunities targeting CSCs. The meeting enabled intriguing discussions on several topics including: genetics and epigenetics; cancer origin and evolution; microenvironment and exosomes; metabolism and inflammation; metastasis and therapy resistance; single cell and heterogeneity; plasticity and reprogramming; as well as other new concepts. Reports of clinical trials targeting CSCs emphasized the urgent need for strategically designing combinational CSC-targeting therapies against cancer.

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The tumor suppressor prostate apoptosis response-4 (Par-4) is regulated by mutant IDH1 and kills glioma stem cells

Cited by 17 publications

References 57 publications

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

Differential expression of the TWEAK receptor Fn14 in IDH1 wild-type and mutant gliomas

Mutant IDH1 and thrombosis in gliomas

Cancer Stem Cells: Targeting the Roots of Cancer, Seeds of Metastasis, and Sources of Therapy Resistance

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