Wild-type and mutated IDH1/2 enzymes and therapy responses

Molenaar, Remco J.; Maciejewski, Jaroslaw P.; Wilmink, Johanna W.; Noorden, C. J. F. Van

doi:10.1038/s41388-017-0077-z

Cited by 188 publications

(183 citation statements)

References 98 publications

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“…Analysis of CPT1-isoform expression revealed increased expression of CPT1A in IDH1 mutant cultures relative to IDH wildtype cells. 13 C-palmitic acid revealed extensive FA utilization throughout the metabolomes of both IDH mutant and WT cells. However, the effects of FAO inhibition with ETOM was more pronounced within the TCA cycle of IDH WT cells.…”

Section: Discussionmentioning

confidence: 97%

“…To further determine how and where FAs are utilized within U87 cells, untreated CNTL cells, cells treated with ETOM, and cells with CPT1A knockdown were subjected to LC-MS metabolomic analysis using fully-labeled 13 C palmitic acid in physiological glucose conditions (2.5 mM). Analyzing fractional contribution (or the percent of labeled carbons for each metabolite) within these samples revealed labeling throughout the TCA cycle as well as in the ubiquitously important currency metabolite ATP.…”

Section: Fatty Acid and Ketone Oxidation In U87mentioning

confidence: 99%

“…Wildtype metabolic function of these enzymes is primarily restricted to the TCA cycle where they produce alpha-ketoglutarate through the oxidative decarboxylation of isocitrate.However, these enzymes often incur neomorphic gain-of-function mutations that result in the production of 2-hydroxyglutarate (2-HG) 11 , a proposed oncometabolite, along with widespread changes that extend far beyond the TCA cycle. The effects of IDH mutations have been attributed to altered glucose and nucleotide metabolism, DNA repair capacity, and reactive oxygen species (ROS) regulation, to name a few 12,13,14 . Thus, the mutations present in any given tumor (such as EGFR, PTEN, and IDH1) may determine the extent to which it can adjust to declining substrate availability, pathway inhibition, or therapeutic insult.…”

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confidence: 99%

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Glioblastoma utilizes fatty acids and ketone bodies for growth allowing progression during ketogenic diet therapy

Sperry

Condro²,

Guo

et al. 2019

Preprint

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Glioblastoma (GBM) metabolism has traditionally been characterized by a dependence on aerobic glycolysis, prompting use of the ketogenic diet as a potential therapy. We observed growth-promoting effects on U87 GBM of both ketone body and fatty acid (FA) supplementation under physiological glucose conditions. An in vivo assessment of the unrestricted ketogenic diet surprisingly resulted in increased tumor growth and decreased animal survival. These effects are abrogated by FAO inhibition using knockdown of carnitine palmitoyltransferase 1 (CPT1).Primary patient GBM cultures revealed significant utilization of FAO regardless of tumorigenic mutational status and decreased proliferation, increased apoptosis, and elevated mitochondrial ROS production with CPT1 inhibition. Metabolomic tracing with 13 C-labeled fatty acids showed significant FA utilization within the TCA cycle, indicating that FAO is used for both bioenergetics and production of key intermediates. These data demonstrate important roles for FA and ketone body metabolism that could serve to improve targeted therapies in GBM.traditionally characterized by its reliance on the Warburg effect. Under normal physiological conditions the healthy adult brain meets most of its energy demand by complete oxidation of glucose. This produces pyruvate which is then converted into acetyl-CoA for entrance into the TCA cycle to support the electron transport chain 1 . Thus, glycolysis and respiration remain tightly connected and result in more efficient ATP production with little lactic acid production. In contrast, the Warburg effect dramatically increases the rate of aerobic glycolysis and lactic acid production in the cytosol. While the benefits of this phenomenon are not completely understood, it has been posited that its main advantages are increased biomass production and facilitated invasion due to acidification of the microenvironment 2 .GBMs have been identified as highly reliant on aerobic glycolysis to the point that they are sometimes referred to as being "glucose addicted". Several common signaling pathways found to be altered in GBM, such as PI3K-Akt-mTOR and Myc pathways, promote this phenotype by increasing expression of genes that allow cells to take up large amounts of glucose for increased glycolysis and lactate production 1, 3, 4 . Alterations to these pathways are often associated with mutations common to GBM such as EGFR and PTEN. EGFR, an activator of PI3K, is amplified in ~40% of GBMs with approximately half of those tumors expressing the constitutively active EGFRviii variant 5 . The tumor suppressor protein PTEN, a potent PI3K antagonist, is also altered in 30-40% of GBMs 6 . Similar to EGFR amplification, loss of PTEN function by either mutation or deletion results in hyperactivation of the PI3K/Akt signaling network. Despite these findings, little progress has been made therapeutically in targeting enzymes reported to regulate glucose metabolism in GBM.The interconnection between oncogenic signaling networks and metabolic pathways is complex in...

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Section: Discussionmentioning

confidence: 97%

Section: Fatty Acid and Ketone Oxidation In U87mentioning

confidence: 99%

mentioning

confidence: 99%

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Glioblastoma utilizes fatty acids and ketone bodies for growth allowing progression during ketogenic diet therapy

Sperry

Condro²,

Guo

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…We curated a list of 100 genes (Supplementary Figure 2A. One of the RT-PCR validated ASE prostate cancer genes is IDH1, a key metabolic gene regulating TET2 mediated epigenetic re-programing in prostate tumor cells 39,40 . We found that casodex treatment of all three prostate cancer cell lines resulted in a switch from ENST00000345146, a dominant transcript of IDH1 to ENST00000415913 with an alternate 5'UTR ( Supplementary Figure 1).…”

Section: Functional Analysis Of Genes Regulated At the Level Of Altermentioning

confidence: 99%

Androgen Receptor Signaling Regulates the Transcriptome of Prostate Cancer Cells by Modulating Global Alternative Splicing

Shah

Gagliano

Garland

et al. 2019

Preprint

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Androgen receptor (AR), is a transcription factor and a member of a hormone receptor superfamily. AR plays a vital role in the progression of prostate cancer and is a crucial target for therapeutic interventions. While the majority of advanced-stage prostate cancer patients will initially respond to the androgen-deprivation, the disease often progresses to castrate-resistant prostate cancer (CRPC). Interestingly, CRPC tumors continue to depend on hyperactive AR signaling and will respond to potent second-line anti-androgen therapies, including bicalutamide (CASODEX Ò ) and enzalutamide (XTANDI Ò ). However, the progression-free survival rate for the CRPC patients on antiandrogen therapies is only 8 to 19 months. Hence, there is a need to understand the mechanisms underlying CRPC progression and eventual treatment resistance. Here, we have leveraged next-generation sequencing and newly developed analytical methodologies to evaluate the role of AR-signaling in regulating the transcriptome of prostate cancer cells. The genomic and pharmacologic stimulation-and inhibition-of AR activity demonstrates that AR regulates alternative splicing within cancer-relevant genes.Furthermore, by integrating transcriptomic data from in vitro experiments and in prostate cancer patients, we found that a significant number of AR-regulated splicing events are associated with tumor progression. For example, we found evidence for an inadvertent AR-antagonist mediated switch in IDH1 and PL2G2A isoform expression, which is associated with a decrease in overall survival of patients. Mechanistically, we discovered that the epithelial-specific splicing regulators (ESRP1 and ESRP2), flank many ARregulated alternatively spliced exons. And, using 2D-invasion assays, we show that the inhibition of ESRPs can suppress AR-antagonist driven tumor invasion. In conclusion, until now, AR signaling has been primarily thought to modulate transcriptome of prostate epithelial cells by inducing or suppressing gene expression. Our work provides evidence for a new mechanism by which AR alters the transcriptome of prostate cancer cells by modulating alternative splicing. As such, our work has important implications for CRPC progression and development of resistance to treatment with bicalutamide and enzalutamide.

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“…By contrast, wildtype IDH1 promotes the metabolic adaptation of GBM cells to support aggressive growth (5). Therefore, it has been proposed that the balance between wild-type and mutant IDH1/2 function determines the clinical outcome of gliomas, including their sensitivity to radiation and chemotherapy (6).…”

Section: Introductionmentioning

confidence: 99%

The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness

Gargini

Segura-Collar

Herránz

et al. 2019

Preprint

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One Sentence SummaryTau, which is induced by IDH mutations, inhibits the EGFR/NF-kB/TAZ axis and impairs the mesenchymal/pericyte-like transformation of glioma cells, normalizing the vasculature and impairing tumor aggressiveness. AbstractMutant IDH1/2 gliomas represent a more indolent form of cancer. However, how this group of tumors evolve, in a microenvironment-dependent manner, is still a pending question. Here we describe that the expression of Tau, a gene classically associated with neurodegenerative diseases, is epigenetically controlled by the balance between wild-type and mutant IDH1/2 in gliomas. Moreover, the level of Tau decreases when the tumor progresses. Besides, Tau is almost absent from tumors with EGFR mutations, whereas its expression is inversely correlated with overall survival in gliomas carrying wild-type or amplified EGFR. Here, we demonstrate that the overexpression of Tau, through the stabilization of microtubules, impairs the mesenchymal/pericyte-like transformation of glioma cells by blocking the EGFR-NFB-TAZ axis. However, mutant EGFR induces a constitutive activation of this pathway, which is no longer sensitive to Tau. By inhibiting the phenotypic plasticity of EGFRamp/wt glioma cells, Tau protein inhibits angiogenesis and favors vascular normalization, decreasing tumor aggressiveness and rendering the tumors more sensitive to chemotherapy.

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Wild-type and mutated IDH1/2 enzymes and therapy responses

Cited by 188 publications

References 98 publications

Glioblastoma utilizes fatty acids and ketone bodies for growth allowing progression during ketogenic diet therapy

Glioblastoma utilizes fatty acids and ketone bodies for growth allowing progression during ketogenic diet therapy

Androgen Receptor Signaling Regulates the Transcriptome of Prostate Cancer Cells by Modulating Global Alternative Splicing

The IDH-Tau-EGFR triad defines diffuse glioma pathology by controlling mesenchymal differentiation and neo-vascular fitness

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