scholarly journals Radiosensitization and a Less Aggressive Phenotype of Human Malignant Glioma Cells Expressing Isocitrate Dehydrogenase 1 (IDH1) Mutant Protein: Dissecting the Mechanisms

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 889 ◽  
Author(s):  
Jacqueline Kessler ◽  
Tim Hohmann ◽  
Antje Güttler ◽  
Marina Petrenko ◽  
Christian Ostheimer ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Isocitrate Dehydrogenase ◽  
Idh1 Mutation ◽  
Cell Stiffness ◽  
Diffuse Glioma ◽  
Isocitrate Dehydrogenase 1 ◽  
Aggressive Phenotype ◽  
Γh2ax Foci ◽  
Mutant Idh1

The presence of an isocitrate dehydrogenase 1 (IDH1) mutation is associated with a less aggressive phenotype, increased sensitivity to radiation, and increased overall survival in patients with diffuse glioma. Based on in vitro experimentations in malignant glioma cell lines, the consequences on cellular processes of IDH1R132H expression were analyzed. The results revealed that IDH1R132H expression enhanced the radiation induced accumulation of residual γH2AX foci and decreased the amount of glutathione (GSH) independent of the oxygen status. In addition, expression of the mutant IDH1 caused a significant increase of cell stiffness and induced an altered organization of the cytoskeleton, which has been shown to reinforce cell stiffness. Furthermore, IDH1R132H expression decreased the expression of vimentin, an important component of the cytoskeleton and regulator of the cell stiffness. The results emphasize the important role of mutant IDH1 in treatment of patients with diffuse gliomas especially in response to radiation. Hence, detection of the genetic status of IDH1 before therapy massively expands the utility of immunohistochemistry to accurately distinguish patients with a less aggressive and radiosensitive IDH1-mutant diffuse glioma suitable for radiotherapy from those with a more aggressive IDH1-wildtype diffuse glioma who might benefit from an individually intensified therapy comprising radiotherapy and alternative medical treatments.

scholarly journals Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants

2018 ◽  
Vol 475 (20) ◽  
pp. 3221-3238 ◽  
Author(s):  
Diego Avellaneda Matteo ◽  
Grace A. Wells ◽  
Lucas A. Luna ◽  
Adam J. Grunseth ◽  
Olga Zagnitko ◽  
...  
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Resistance Mutation ◽  
Poor Response ◽  
Fold Increase ◽  
Structural Features ◽  
Low Grade ◽  
Wild Type ◽  
Isocitrate Dehydrogenase 1 ◽  
Dynamics Simulations ◽  
Mutant Idh1

Mutations in isocitrate dehydrogenase 1 (IDH1) drive most low-grade gliomas and secondary glioblastomas and many chondrosarcomas and acute myeloid leukemia cases. Most tumor-relevant IDH1 mutations are deficient in the normal oxidization of isocitrate to α-ketoglutarate (αKG), but gain the neomorphic activity of reducing αKG to D-2-hydroxyglutarate (D2HG), which drives tumorigenesis. We found previously that IDH1 mutants exhibit one of two reactivities: deficient αKG and moderate D2HG production (including commonly observed R132H and R132C) or moderate αKG and high D2HG production (R132Q). Here, we identify a third type of reactivity, deficient αKG and high D2HG production (R132L). We show that R132Q IDH1 has unique structural features and distinct reactivities towards mutant IDH1 inhibitors. Biochemical and cell-based assays demonstrate that while most tumor-relevant mutations were effectively inhibited by mutant IDH1 inhibitors, R132Q IDH1 had up to a 16 300-fold increase in IC50 versus R132H IDH1. Only compounds that inhibited wild-type (WT) IDH1 were effective against R132Q. This suggests that patients with a R132Q mutation may have a poor response to mutant IDH1 therapies. Molecular dynamics simulations revealed that near the NADP+/NADPH-binding site in R132Q IDH1, a pair of α-helices switches between conformations that are more wild-type-like or more mutant-like, highlighting mechanisms for preserved WT activity. Dihedral angle changes in the dimer interface and buried surface area charges highlight possible mechanisms for loss of inhibitor affinity against R132Q. This work provides a platform for predicting a patient's therapeutic response and identifies a potential resistance mutation that may arise upon treatment with mutant IDH inhibitors.

scholarly journals Detection of Metabolic Changes Induced via Drug Treatments in Live Cancer Cells and Tissue Using Raman Imaging Microscopy

Biosensors ◽  
2018 ◽  
Vol 9 (1) ◽  
pp. 5 ◽  
Author(s):  
Mioara Larion ◽  
Tyrone Dowdy ◽  
Victor Ruiz-Rodado ◽  
Matthew Meyer ◽  
Hua Song ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Idh1 Mutation ◽  
Raman Imaging ◽  
Metabolic Changes ◽  
Isocitrate Dehydrogenase 1 ◽  
Fibrosarcoma Cells ◽  
Drug Treatments

Isocitrate dehydrogenase 1 (IDH1) mutations in gliomas, fibrosarcoma, and other cancers leads to a novel metabolite, D-2-hydroxyglutarate, which is proposed to cause tumorigenesis. The production of this metabolite also causes vulnerabilities in cellular metabolism, such as lowering NADPH levels. To exploit this vulnerability, we treated glioma and fibrosarcoma cells that harbor an IDH1 mutation with an inhibitor of nicotinamide adenine dinucleotide (NAD+) salvage pathway, FK866, and observed decreased viability in these cells. To understand the mechanism of action by which the inhibitor FK866 works, we used Raman imaging microscopy and identified that proteins and lipids are decreased upon treatment with the drug. Raman imaging showed a different distribution of lipids throughout the cell in the presence of the drug compared with the untreated cells. We employed nuclear magnetic resonance NMR spectroscopy and mass spectrometry to identify the classes of lipids altered. Our combined analyses point to a decrease in cell division due to loss of lipid content that contributes to membrane formation in the in vitro setting. However, the FK866 drug did not have the same potency in vivo. The use of Raman imaging microscopy indicated an opposite trend of lipid distribution in the tissue collected from treated versus untreated mice when compared with the cells. These results demonstrate the role of Raman imaging microscopy to identify and quantify metabolic changes in cancer cells and tissue.

scholarly journals Mutant IDH1 Differently Affects Redox State and Metabolism in Glial Cells of Normal and Tumor Origin

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2028 ◽  
Author(s):  
Julia Biedermann ◽  
Matthias Preussler ◽  
Marina Conde ◽  
Mirko Peitzsch ◽  
Susan Richter ◽  
...  
Keyword(s):  
Redox State ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Idh1 Mutation ◽  
The Cancer Genome Atlas ◽  
Low Grade ◽  
Dependent Manner ◽  
Glioblastoma Cells ◽  
Isocitrate Dehydrogenase 1 ◽  
Nicotinamide Phosphoribosyltransferase

IDH1R132H (isocitrate dehydrogenase 1) mutations play a key role in the development of low-grade gliomas. IDH1wt converts isocitrate to α-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+), whereas IDH1R132H uses α-ketoglutarate and NADPH to generate the oncometabolite 2-hydroxyglutarate (2-HG). While the effects of 2-HG have been the subject of intense research, the 2-HG independent effects of IDH1R132H are still ambiguous. The present study demonstrates that IDH1R132H expression but not 2-HG alone leads to significantly decreased tricarboxylic acid (TCA) cycle metabolites, reduced proliferation, and enhanced sensitivity to irradiation in both glioblastoma cells and astrocytes in vitro. Glioblastoma cells, but not astrocytes, showed decreased NADPH and NAD+ levels upon IDH1R132H transduction. However, in astrocytes IDH1R132H led to elevated expression of the NAD-synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). These effects were not 2-HG mediated. This suggests that IDH1R132H cells utilize NAD+ to restore NADP pools, which only astrocytes could compensate via induction of NAMPT. We found that the expression of NAMPT is lower in patient-derived IDH1-mutant glioma cells and xenografts compared to IDH1-wildtype models. The Cancer Genome Atlas (TCGA) data analysis confirmed lower NAMPT expression in IDH1-mutant versus IDH1-wildtype gliomas. We show that the IDH1 mutation directly affects the energy homeostasis and redox state in a cell-type dependent manner. Targeting the impairments in metabolism and redox state might open up new avenues for treating IDH1-mutant gliomas.

scholarly journals Mutant Isocitrate Dehydrogenase 1 Disrupts PKM2–β-Catenin–BRG1 Transcriptional Network-Driven CD47 Expression

2018 ◽  
Vol 38 (9) ◽  
Author(s):  
Pruthvi Gowda ◽  
Shruti Patrick ◽  
Ankita Singh ◽  
Touseef Sheikh ◽  
Ellora Sen
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Chromatin Immunoprecipitation ◽  
Immune Surveillance ◽  
Ectopic Expression ◽  
The Cancer Genome Atlas ◽  
Data Sets ◽  
Isocitrate Dehydrogenase 1 ◽  
Idh1 R132h ◽  
Cancer Genome Atlas ◽  
Mutant Idh1

ABSTRACT A gain-of-function mutation in isocitrate dehydrogenase 1 (IDH1) affects immune surveillance in gliomas. As elevated CD47 levels are associated with immune evasion in cancers, its status in gliomas harboring mutant IDH1 (IDH1-MT cells) was investigated. Decreased CD47 expression in IDH1-R132H-overexpressing cells was accompanied by diminished nuclear β-catenin, pyruvate kinase isoform M2 (PKM2), and TCF4 levels compared to those in cells harboring wild-type IDH1 (IDH1-WT cells). The inhibition of β-catenin in IDH1-WT cells abrogated CD47 expression, β-catenin–TCF4 interaction, and the transactivational activity of β-catenin/TCF4. The reverse effect was observed in IDH1-MT cells upon the pharmacological elevation of nuclear β-catenin levels. Genetic and pharmacological manipulation of nuclear PKM2 levels in IDH1-WT and IDH1-MT cells suggested that PKM2 is a positive regulator of the β-catenin–TCF4 interaction. The Cancer Genome Atlas (TCGA) data sets indicated diminished CD47, PKM2, and β-catenin levels in IDH1-MT gliomas compared to IDH1-WT gliomas. Also, elevated BRG1 levels with mutations in the ATP-dependent chromatin-remodeling site were observed in IDH1-MT glioma. The ectopic expression of ATPase-deficient BRG1 diminished CD47 expression as well as TCF4 occupancy on its promoter. Sequential chromatin immunoprecipitation (ChIP–re-ChIP) revealed the recruitment of the PKM2–β-catenin–BRG1–TCF4 complex to the TCF4 site on the CD47 promoter. This occupancy translated into CD47 transcription, as a diminished recruitment of this complex was observed in glioma cells bearing IDH1-R132H. In addition to its involvement in CD47 transcriptional regulation, PKM2–β-catenin–BRG1 cross talk affected the phagocytosis of IDH1-MT cells by microglia.

Isocitrate Dehydrogenase 1 Codon 132 Mutation Is an Important Prognostic Biomarker in Gliomas

2009 ◽  
Vol 27 (25) ◽  
pp. 4150-4154 ◽  
Author(s):  
Marc Sanson ◽  
Yannick Marie ◽  
Sophie Paris ◽  
Ahmed Idbaih ◽  
Julien Laffaire ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Isocitrate Dehydrogenase ◽  
Prognostic Biomarker ◽  
Methylation Status ◽  
Idh1 Mutation ◽  
Mgmt Promoter Methylation ◽  
Genomic Profile ◽  
Isocitrate Dehydrogenase 1 ◽  
Egfr Amplification ◽  
Grade 3

Purpose Unexpected mutations affecting the isocitrate dehydrogenase (IDH1) gene at codon 132 have been found in 12% of glioblastomas. Patients and Methods IDH1 codon 132 sequencing was performed in a series of 404 patients with glioma (100 grade 2, 121 grade 3, and 183 grade 4 gliomas) and correlated with histology, genomic profile, methylguanyl methyltransferase (MGMT) promoter methylation status, and outcome. Results A total of 155 codon 132 mutations were found, of which 131 were Arg132His (88.5%). The IDH1 mutation was inversely correlated with grade, affecting 77% of grade 2, 55% of grade 3, and 6% of grade 4 gliomas (P < 10−15). The IDH1 mutation was tightly associated with a 1p19q codeleted genotype (P < 10−14) and an MGMT methylated status (P < .001) but mutually exclusive with EGFR amplification (P < 10−15) and loss of chromosome 10 (P < 10−15). The presence (v absence) of IDH1 mutation was associated with a better outcome in grade 2 (150.9 v 60.1 months, respectively; P = .01), grade 3 (81.1 v 19.4 months, respectively; P < .001), and grade 4 gliomas (27.4 v 14 months, respectively; P < .01). After adjustment for grade, age, MGMT status, genomic profile, and treatment, multivariate analysis confirmed that IDH1 mutation was an independent favorable prognostic marker (hazard ratio = 0.297; 95% CI, 0.157 to 0.564, P = .00021). Conclusion This study indicates that IDH1 codon 132 mutation is closely linked to the genomic profile of the tumor and constitutes an important prognostic marker in grade 2 to 4 gliomas.

scholarly journals Sphere-Forming Culture for Expanding Genetically Distinct Patient-Derived Glioma Stem Cells by Cellular Growth Rate Screening

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 549
Author(s):  
Kayoung Shin ◽  
Hyemi Shin ◽  
Hee Jin Cho ◽  
Hyunju Kang ◽  
Jin-Ku Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Growth Factor ◽  
Growth Rates ◽  
Isocitrate Dehydrogenase ◽  
Cellular Growth ◽  
Glioma Stem Cells ◽  
In Vitro Cultivation ◽  
Isocitrate Dehydrogenase 1 ◽  
Wide Range

Diffusely infiltrating gliomas (DIGs) are difficult to completely resect and are associated with a high rate of tumor relapse and progression from low- to high-grade glioma. In particular, optimized short-term culture-enriching patient-derived glioma stem cells (GSCs) are essential for customizing the therapeutic strategy based on clinically feasible in vitro drug screening for a wide range of DIGs, owing to the high inter-tumoral heterogeneity. Herein, we constructed a novel high-throughput culture condition screening platform called ‘GFSCAN’, which evaluated the cellular growth rates of GSCs for each DIG sample in 132 serum-free combinations, using 13 previously reported growth factors closely associated with glioma aggressiveness. In total, 72 patient-derived GSCs with available genomic profiles were tested in GFSCAN to explore the association between cellular growth rates in specific growth factor combinations and genomic/molecular backgrounds, including isocitrate dehydrogenase 1 (IDH1) mutation, chromosome arm 1p and 19q co-deletion, ATRX chromatin remodeler alteration, and transcriptional subtype. GSCs were clustered according to the dependency on epidermal growth factor and basic fibroblast growth factor (E&F), and isocitrate dehydrogenase 1 (IDH1) wild-type GSCs showed higher E&F dependencies than IDH1 mutant GSCs. More importantly, we elucidated optimal combinations for IDH1 mutant glioblastoma and lower grade glioma GSCs with low dependencies on E&F, which could be an aid in clinical decision-making for these DIGs. Thus, we demonstrated the utility of GFSCAN in personalizing in vitro cultivation to nominate personalized therapeutic options, in a clinically relevant time frame, for individual DIG patients, where standard clinical options have been exhausted.

scholarly journals Up-regulated isocitrate dehydrogenase 1 suppresses proliferation, migration and invasion in osteosarcoma: In vitro and in vivo

2014 ◽  
Vol 346 (1) ◽  
pp. 114-121 ◽  
Author(s):  
Xiang Hu ◽  
Yang Liu ◽  
Chunxia Qin ◽  
Zhenyu Pan ◽  
Jun Luo ◽  
...  
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Migration And Invasion ◽  
Isocitrate Dehydrogenase 1

Isocitrate dehydrogenase-1 mutations: a fundamentally new understanding of diffuse glioma?

2011 ◽  
Vol 12 (1) ◽  
pp. 83-91 ◽  
Author(s):  
Nanne K Kloosterhof ◽  
Linda BC Bralten ◽  
Hendrikus J Dubbink ◽  
Pim J French ◽  
Martin J van den Bent
Keyword(s):  
Isocitrate Dehydrogenase ◽  
Diffuse Glioma ◽  
Isocitrate Dehydrogenase 1

scholarly journals Assessment of Isocitrate Dehydrogenase 1 Mutation by Immunohistochemistry in Egyptian Patients with High-grade Gliomas

2021 ◽  
Vol 9 (A) ◽  
pp. 157-163
Author(s):  
Essam Ayad ◽  
Sylvia Mikhael Ghattas ◽  
Rabab Abdel Moneim ◽  
Azzam Ismail ◽  
Rasha A. Khairy
Keyword(s):  
Significant Relationship ◽  
Isocitrate Dehydrogenase ◽  
Progression Free Survival ◽  
High Grade Glioma ◽  
Idh1 Mutation ◽  
Response To Treatment ◽  
High Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
High Grade Gliomas ◽  
Grade Iii

BACKGROUND: At present, the classification of central nervous system tumors relies on molecular factors in addition to histologic features to identify many tumor types. This should subsequently results in more accurate diagnosis as well as addressing specific markers of potential prognostic and predictive value. AIM: This study was conducted to emphasize the importance of including isocitrate dehydrogenase 1 (IDH1) evaluation as a crucial part of the diagnosis and categorization of high-grade glioma cases. This also may help to individualize the treatment of high-grade glioma patients. MATERIALS AND METHODS: The current study included 60 cases of high-grade gliomas, studied histologically and immunohistochemically for the detection of IDH1 mutation. The results were correlated with different clinicopathologic variables and course of the disease. RESULTS: IDH1 immunohistochemical expression was positive in 46.67% of the studied high-grade glioma cases. A statistically significant relationship was detected between IDH1 expression and tumor histologic grade as 100% of Grade III anaplastic oligodendroglioma cases and 80% of the Grade III anaplastic astrocytoma cases were IDH1 positive while only 40.4% of Grade IV glioblastoma cases were IDH1 positive (p = 0.03). In addition, patients who were IDH1 mutant were in a better category of response to radiotherapy (p = 0.019) and also to chemotherapy (p < 0.001). Moreover, patients who expressed IDH1 had prolonged overall survival (OS) and progression-free survival than those who showed negative IDH1expression (p < 0.001). On the other hand, no statistically significant relationship was detected between IDH1 expression and patients age, sex, tumor site, tumor size, motor symptoms, sensory symptoms, and increased intracranial tension (p > 0.05). CONCLUSIONS: It is suggested that IDH1 is a good prognostic marker for gliomas and is a good predictive marker for response to treatment. IDH1 is a promising target for therapy in high-grade gliomas through the emerging IDH1 inhibitors. Immunohistochemical testing for IDH1 is a practical and cost-effective method that should be applied in all glioma cases. Further study on a larger sample size is recommended to validate the current results. Moreover, applying molecular analysis to detect IDH1 mutation is recommended to be able to precisely detect the IDH1 wild-type tumor

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