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1.
Cancer Cell ; 37(2): 147-156, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32049045

RESUMO

Metabolic pathways must be adapted to support cell processes required for transformation and cancer progression. Amino acid metabolism is deregulated in many cancers, with changes in branched-chain amino acid metabolism specifically affecting cancer cell state as well as systemic metabolism in individuals with malignancy. This review highlights key concepts surrounding the current understanding of branched-chain amino acid metabolism and its role in cancer.

2.
FEBS Lett ; 594(4): 646-664, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31642061

RESUMO

Mammalian pyruvate kinase catalyzes the final step of glycolysis, and its M2 isoform (PKM2) is widely expressed in proliferative tissues. Mutations in PKM2 are found in some human cancers; however, the effects of these mutations on enzyme activity and regulation are unknown. Here, we characterized five cancer-associated PKM2 mutations, occurring at various locations on the enzyme, with respect to substrate kinetics and activation by the allosteric activator fructose-1,6-bisphosphate (FBP). The mutants exhibit reduced maximal velocity, reduced substrate affinity, and/or altered activation by FBP. The kinetic parameters of five additional PKM2 mutants that have been used to study enzyme function or regulation also demonstrate the deleterious effects of mutations on PKM2 function. Our findings indicate that PKM2 is sensitive to many amino acid changes and support the hypothesis that decreased PKM2 activity is selected for in rapidly proliferating cells.

3.
Nat Commun ; 10(1): 5604, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31811141

RESUMO

Increased glucose uptake and metabolism is a prominent phenotype of most cancers, but efforts to clinically target this metabolic alteration have been challenging. Here, we present evidence that lactoylglutathione (LGSH), a byproduct of methylglyoxal detoxification, is elevated in both human and murine non-small cell lung cancers (NSCLC). Methylglyoxal is a reactive metabolite byproduct of glycolysis that reacts non-enzymatically with nucleophiles in cells, including basic amino acids, and reduces cellular fitness. Detoxification of methylglyoxal requires reduced glutathione (GSH), which accumulates to high levels in NSCLC relative to normal lung. Ablation of the methylglyoxal detoxification enzyme glyoxalase I (Glo1) potentiates methylglyoxal sensitivity and reduces tumor growth in mice, arguing that targeting pathways involved in detoxification of reactive metabolites is an approach to exploit the consequences of increased glucose metabolism in cancer.

4.
Trends Cancer ; 5(12): 762-765, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31813453

RESUMO

Tumour dormancy presents challenges for clinical control and opportunities for scientific discovery. Current pictures of the mechanisms of tumour dormancy and reawakening remain incomplete. The Cancer Research UK's third Marshall Symposium explored tumour dormancy and reawakening in all their forms. In this forum article, we highlight the key challenges and opportunities discussed at this symposium.

5.
Sci Transl Med ; 11(517)2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694929

RESUMO

Small cell lung cancer (SCLC) is an aggressive lung cancer subtype with extremely poor prognosis. No targetable genetic driver events have been identified, and the treatment landscape for this disease has remained nearly unchanged for over 30 years. Here, we have taken a CRISPR-based screening approach to identify genetic vulnerabilities in SCLC that may serve as potential therapeutic targets. We used a single-guide RNA (sgRNA) library targeting ~5000 genes deemed to encode "druggable" proteins to perform loss-of-function genetic screens in a panel of cell lines derived from autochthonous genetically engineered mouse models (GEMMs) of SCLC, lung adenocarcinoma (LUAD), and pancreatic ductal adenocarcinoma (PDAC). Cross-cancer analyses allowed us to identify SCLC-selective vulnerabilities. In particular, we observed enhanced sensitivity of SCLC cells toward disruption of the pyrimidine biosynthesis pathway. Pharmacological inhibition of dihydroorotate dehydrogenase (DHODH), a key enzyme in this pathway, reduced the viability of SCLC cells in vitro and strongly suppressed SCLC tumor growth in human patient-derived xenograft (PDX) models and in an autochthonous mouse model. These results indicate that DHODH inhibition may be an approach to treat SCLC.

6.
Nat Metab ; 1(9): 861-867, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31598584

RESUMO

The de novo serine synthesis pathway is upregulated in many cancers. However, even cancer cells with increased serine synthesis take up large amounts of serine from the environment1 and we confirm that exogenous serine is needed for maximal proliferation of these cells. Here we show that even when enzymes in the serine synthesis pathway are genetically upregulated, the demand for oxidized NAD+ constrains serine synthesis, rendering serine-deprived cells sensitive to conditions that decrease the cellular NAD+/NADH ratio. Further, purine depletion is a major consequence of reduced intracellular serine availability, particularly when NAD+ regeneration is impaired. Thus, cells rely on exogenous serine consumption to maintain purine biosynthesis. In support of this explanation, providing exogenous purine nucleobases, or increasing NAD+ availability to facilitate de novo serine and purine synthesis, both rescue maximal proliferation even in the absence of extracellular serine. Together, these data indicate that NAD+ is an endogenous limitation for cancer cells to synthesize the serine needed for purine production to support rapid proliferation.

7.
Cancer Epidemiol Biomarkers Prev ; 28(12): 2062-2069, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31533940

RESUMO

BACKGROUND: Pancreatic cancer is associated with development of cachexia, a wasting syndrome thought to limit survival. Few studies have longitudinally quantified peripheral tissues or identified biomarkers predictive of future tissue wasting. METHODS: Adipose and muscle tissue were measured by computed tomography (CT) at diagnosis and 50 to 120 days later in 164 patients with advanced pancreatic cancer. Tissue changes and survival were evaluated by Cox proportional hazards regression. Baseline levels of circulating markers were examined in relation to future tissue wasting. RESULTS: Compared with patients in the bottom quartile of muscle change per 30 days (average gain of 0.8 ± 2.0 cm2), those in the top quartile (average loss of 12.9 ± 4.9 cm2) had a hazard ratio (HR) for death of 2.01 [95% confidence interval (CI), 1.12-3.62]. Patients in the top quartile of muscle attenuation change (average decrease of 4.9 ± 2.4 Hounsfield units) had an HR of 2.19 (95% CI, 1.18-4.04) compared with those in the bottom quartile (average increase of 2.4 ± 1.6 Hounsfield units). Changes in adipose tissue were not associated with survival. Higher plasma branched chain amino acids (BCAA; P = 0.004) and lower monocyte chemoattractant protein-1 (MCP-1; P = 0.005) at diagnosis were associated with greater future muscle loss. CONCLUSIONS: In patients with advanced pancreatic cancer, muscle loss and decrease in muscle density in 2 to 4 months after diagnosis were associated with reduced survival. BCAAs and MCP-1 levels at diagnosis were associated with subsequent muscle loss. IMPACT: BCAAs and MCP-1 levels at diagnosis could identify a high-risk group for future tissue wasting.

8.
Cancer Res ; 79(22): 5723-5733, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31484670

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer deaths in the United States. The deoxynucleoside analogue gemcitabine is among the most effective therapies to treat PDAC, however, nearly all patients treated with gemcitabine either fail to respond or rapidly develop resistance. One hallmark of PDAC is a striking accumulation of stromal tissue surrounding the tumor, and this accumulation of stroma can contribute to therapy resistance. To better understand how stroma limits response to therapy, we investigated cell-extrinsic mechanisms of resistance to gemcitabine. Conditioned media from pancreatic stellate cells (PSC), as well as from other fibroblasts, protected PDAC cells from gemcitabine toxicity. The protective effect of PSC-conditioned media was mediated by secretion of deoxycytidine, but not other deoxynucleosides, through equilibrative nucleoside transporters. Deoxycytidine inhibited the processing of gemcitabine in PDAC cells, thus reducing the effect of gemcitabine and other nucleoside analogues on cancer cells. These results suggest that reducing deoxycytidine production in PSCs may increase the efficacy of nucleoside analog therapies. SIGNIFICANCE: This study provides important new insight into mechanisms that contribute to gemcitabine resistance in PDAC and suggests new avenues for improving gemcitabine efficacy.

9.
Nat Rev Cancer ; 19(11): 651-661, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31530936

RESUMO

The way cancer cells utilize nutrients to support their growth and proliferation is determined by cancer cell-intrinsic and cancer cell-extrinsic factors, including interactions with the environment. These interactions can define therapeutic vulnerabilities and impact the effectiveness of cancer therapy. Diet-mediated changes in whole-body metabolism and systemic nutrient availability can affect the environment that cancer cells are exposed to within tumours, and a better understanding of how diet modulates nutrient availability and utilization by cancer cells is needed. How diet impacts cancer outcomes is also of great interest to patients, yet clear evidence for how diet interacts with therapy and impacts tumour growth is lacking. Here we propose an experimental framework to probe the connections between diet and cancer metabolism. We examine how dietary factors may affect tumour growth by altering the access to and utilization of nutrients by cancer cells. Our growing understanding of how certain cancer types respond to various diets, how diet impacts cancer cell metabolism to mediate these responses and whether dietary interventions may constitute new therapeutic opportunities will begin to provide guidance on how best to use diet and nutrition to manage cancer in patients.


Assuntos
Dieta , Metástase Neoplásica , Neoplasias/metabolismo , Neoplasias/patologia , Proliferação de Células , Progressão da Doença , Hormônios/metabolismo , Humanos , Oncologia , Risco , Transdução de Sinais , Resultado do Tratamento
10.
BMC Cancer ; 19(1): 723, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31331318

RESUMO

BACKGROUND: Copy number gain of the D-3-phosphoglycerate dehydrogenase (PHGDH) gene, which encodes the first enzyme in serine biosynthesis, is found in some human cancers including a subset of melanomas. METHODS: In order to study the effect of increased PHGDH expression in tissues in vivo, we generated mice harboring a PHGDHtetO allele that allows tissue-specific, doxycycline-inducible PHGDH expression, and we analyzed the phenotype of mice with a ubiquitous increase in PHGDH expression. RESULTS: Tissues and cells derived from PHGDHtetO mice exhibit increased serine biosynthesis. Histological examination of skin tissue from PHGDHtetO mice reveals the presence of melanin granules in early anagen hair follicles, despite the fact that melanin synthesis is closely coupled to the hair follicle cycle and does not normally begin until later in the cycle. This phenotype occurs in the absence of any global change in hair follicle cycle timing. The aberrant presence of melanin early in the hair follicle cycle following PHGDH expression is also accompanied by increased melanocyte abundance in early anagen skin. CONCLUSIONS: These data suggest increased PHGDH expression impacts normal melanocyte biology, but PHGDH expression alone is not sufficient to cause cancer.


Assuntos
Expressão Gênica , Melaninas/metabolismo , Fosfoglicerato Desidrogenase/genética , Alelos , Animais , Linhagem Celular , Doxiciclina/farmacologia , Folículo Piloso/fisiologia , Humanos , Melanócitos/metabolismo , Melanoma/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Serina/biossíntese , Pele/metabolismo , Neoplasias Cutâneas/metabolismo
11.
Crit Rev Biochem Mol Biol ; 54(3): 193-207, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31162937

RESUMO

Proliferation requires that cells accumulate sufficient biomass to grow and divide. Cancer cells within tumors must acquire a variety of nutrients, and tumor growth slows or stops if necessary metabolites are not obtained in sufficient quantities. Importantly, the metabolic demands of cancer cells can be different from those of untransformed cells, and nutrient accessibility in tumors is different than in many normal tissues. Thus, cancer cell survival and proliferation may be limited by different metabolic factors than those that are necessary to maintain noncancerous cells. Understanding the variables that dictate which nutrients are critical to sustain tumor growth may identify vulnerabilities that could be used to treat cancer. This review examines the various cell-autonomous, local, and systemic factors that determine which nutrients are limiting for tumor growth.


Assuntos
Neoplasias/metabolismo , Nutrientes/metabolismo , Animais , Proliferação de Células , Progressão da Doença , Humanos , Redes e Vias Metabólicas , Mutação , Neoplasias/genética , Neoplasias/patologia , Nutrientes/genética , Necessidades Nutricionais , Microambiente Tumoral
12.
PLoS Biol ; 17(6): e2004413, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31181072

RESUMO

Bcl-2 family proteins control a decisive apoptotic event: mitochondrial outer membrane permeabilization (MOMP). To discover MOMP-regulating proteins, we expressed a library of intracellular single-chain variable fragments (scFvs) ("intrabodies") and selected for those rescuing cells from apoptosis induced by BimS (the short isoform of Bim). One anti-apoptotic intrabody, intrabody 5 (IB5), recognized pyruvate kinase M2 (PKM2), which is expressed in cancer cells. PKM2 deletion ablated this clonogenic rescue; thus, IB5 activated a latent cytoprotective function of PKM2. This resulted not from pyruvate kinase activity per se but rather from the formation of an active tetrameric conformation of PKM2. A stably tetrameric PKM2 mutant, K422R, promoted cell survival even in the absence of IB5, and IB5 further increased survival. Mitochondria isolated from IB5-expressing cells were relatively resistant to MOMP in vitro. In cells, IB5 expression up-regulated Mitofusin-1 (Mfn1) and increased mitochondrial length. Importantly, Mfn1 deficiency abrogated IB5's cytoprotective effect. PKM2's anti-apoptotic function could help explain its preferential expression in human cancer.


Assuntos
Permeabilidade da Membrana Celular/fisiologia , Membranas Mitocondriais/fisiologia , Piruvato Quinase/metabolismo , Sequência de Aminoácidos , Apoptose/fisiologia , Proteína 11 Semelhante a Bcl-2/metabolismo , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , GTP Fosfo-Hidrolases/metabolismo , Biblioteca Gênica , Células HEK293 , Humanos , Proteínas de Membrana/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Isoformas de Proteínas/metabolismo , Piruvato Quinase/fisiologia , Transdução de Sinais , Anticorpos de Cadeia Única
13.
Immunity ; 50(5): 1129-1131, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31117009

RESUMO

Metabolic changes affect T lymphocyte function, and understanding this phenomenon could improve immunotherapy. In a recent paper in Science, Vodnala et al. (2019) report that tumor microenvironmental potassium impairs T cell nutrient uptake and thus causes functional caloric restriction and allows improved anti-tumor immune responses.


Assuntos
Células Matadoras Naturais , Neoplasias , Humanos , Imunoterapia , Linfócitos T , Microambiente Tumoral
14.
Elife ; 82019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30990168

RESUMO

Cancer cell metabolism is heavily influenced by microenvironmental factors, including nutrient availability. Therefore, knowledge of microenvironmental nutrient levels is essential to understand tumor metabolism. To measure the extracellular nutrient levels available to tumors, we utilized quantitative metabolomics methods to measure the absolute concentrations of >118 metabolites in plasma and tumor interstitial fluid, the extracellular fluid that perfuses tumors. Comparison of nutrient levels in tumor interstitial fluid and plasma revealed that the nutrients available to tumors differ from those present in circulation. Further, by comparing interstitial fluid nutrient levels between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma, we found that tumor type, anatomical location and animal diet affect local nutrient availability. These data provide a comprehensive characterization of the nutrients present in the tumor microenvironment of widely used models of lung and pancreatic cancer and identify factors that influence metabolite levels in tumors.

15.
Cell Metab ; 29(6): 1410-1421.e4, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-30905671

RESUMO

Tumors exhibit altered metabolism compared to normal tissues. Many cancers upregulate expression of serine synthesis pathway enzymes, and some tumors exhibit copy-number gain of the gene encoding the first enzyme in the pathway, phosphoglycerate dehydrogenase (PHGDH). However, whether increased serine synthesis promotes tumor growth and how serine synthesis benefits tumors is controversial. Here, we demonstrate that increased PHGDH expression promotes tumor progression in mouse models of melanoma and breast cancer, human tumor types that exhibit PHGDH copy-number gain. We measure circulating serine levels and find that PHGDH expression is necessary to support cell proliferation at lower physiological serine concentrations. Increased dietary serine or high PHGDH expression is sufficient to increase intracellular serine levels and support faster tumor growth. Together, these data suggest that physiological serine availability restrains tumor growth and argue that tumors arising in serine-limited environments acquire a fitness advantage by upregulating serine synthesis pathway enzymes.

16.
Proc Natl Acad Sci U S A ; 116(6): 2232-2236, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30674677

RESUMO

Circulating tumor cells (CTCs) play a fundamental role in cancer progression. However, in mice, limited blood volume and the rarity of CTCs in the bloodstream preclude longitudinal, in-depth studies of these cells using existing liquid biopsy techniques. Here, we present an optofluidic system that continuously collects fluorescently labeled CTCs from a genetically engineered mouse model (GEMM) for several hours per day over multiple days or weeks. The system is based on a microfluidic cell sorting chip connected serially to an unanesthetized mouse via an implanted arteriovenous shunt. Pneumatically controlled microfluidic valves capture CTCs as they flow through the device, and CTC-depleted blood is returned back to the mouse via the shunt. To demonstrate the utility of our system, we profile CTCs isolated longitudinally from animals over 4 days of treatment with the BET inhibitor JQ1 using single-cell RNA sequencing (scRNA-Seq) and show that our approach eliminates potential biases driven by intermouse heterogeneity that can occur when CTCs are collected across different mice. The CTC isolation and sorting technology presented here provides a research tool to help reveal details of how CTCs evolve over time, allowing studies to credential changes in CTCs as biomarkers of drug response and facilitating future studies to understand the role of CTCs in metastasis.


Assuntos
Citometria de Fluxo , Técnicas Analíticas Microfluídicas , Microfluídica , Neoplasias/diagnóstico , Neoplasias/metabolismo , Células Neoplásicas Circulantes/metabolismo , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Citometria de Fluxo/métodos , Perfilação da Expressão Gênica/métodos , Camundongos , Microfluídica/métodos , Neoplasias/genética , Células Neoplásicas Circulantes/patologia , Análise de Célula Única/métodos , Transcriptoma
17.
Cancer Metab ; 6: 17, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386596

RESUMO

Background: While most cancer cells preferentially express the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2), PKM2 is dispensable for tumor development in several mouse cancer models. PKM2 is expressed in human pancreatic cancer, and there have been conflicting reports on the association of PKM2 expression and pancreatic cancer patient survival, but whether PKM2 is required for pancreatic cancer progression is unknown. To investigate the role of PKM2 in pancreatic cancer, we used a conditional allele to delete PKM2 in a mouse model of pancreatic ductal adenocarcinoma (PDAC). Results: PDAC tumors were initiated in LSL-Kras G12D/+ ;Trp53 flox/flox ;Pdx-1-Cre (KP-/-C) mice harboring a conditional Pkm2 allele. Immunohistochemical analysis showed PKM2 expression in wild-type tumors and loss of PKM2 expression in tumors from Pkm2 conditional mice. PKM2 deletion had no effect on overall survival or tumor size. Loss of PKM2 resulted in pyruvate kinase M1 (PKM1) expression, but did not affect the number of proliferating cells. These findings are consistent with results in other cancer models. Conclusions: PKM2 is not required for initiation or growth of PDAC tumors arising in the KP-/-C pancreatic cancer model. These findings suggest that, in this mouse PDAC model, PKM2 expression is not required for pancreatic tumor formation or progression.

18.
J Biol Chem ; 293(52): 20051-20061, 2018 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-30381394

RESUMO

Monoallelic point mutations in the gene encoding the cytosolic, NADP+-dependent enzyme isocitrate dehydrogenase 1 (IDH1) cause increased production of the oncometabolite 2-hydroxyglutarate (2-HG) in multiple cancers. Most IDH1 mutant tumors retain one wildtype (WT) IDH1 allele. Several studies have proposed that retention of this WT allele is protumorigenic by facilitating substrate channeling through a WT-mutant IDH1 heterodimer, with the WT subunit generating a local supply of α-ketoglutarate and NADPH that is then consumed by the mutant subunit to produce 2-HG. Here, we confirmed that coexpression of WT and mutant IDH1 subunits leads to formation of WT-mutant hetero-oligomers and increases 2-HG production. An analysis of a recently reported crystal structure of the WT-R132H IDH1 heterodimer and of in vitro kinetic parameters for 2-HG production, however, indicated that substrate channeling between the subunits is biophysically implausible. We also found that putative carbon-substrate flux between WT and mutant IDH1 subunits is inconsistent with the results of isotope tracing experiments in cancer cells harboring an endogenous monoallelic IDH1 mutation. Finally, using a mathematical model of WT-mutant IDH1 heterodimers, we estimated that the NADPH:NADP+ ratio is higher in the cytosol than in the mitochondria, suggesting that NADPH is unlikely to be limiting for 2-HG production in the cytosol. These findings argue against supply of either substrate being limiting for 2-HG production by a cytosolic IDH1 mutant and suggest that the retention of a WT allele in IDH1 mutant tumors is not due to a requirement for carbon or cofactor flux between WT and mutant IDH1.


Assuntos
Hidroxibutiratos/metabolismo , Isocitrato Desidrogenase , Modelos Biológicos , Mutação , Proteínas de Neoplasias , Neoplasias , Linhagem Celular Tumoral , Células HEK293 , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , NADP/genética , NADP/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Multimerização Proteica
19.
EMBO J ; 37(22)2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30348863

RESUMO

The Hippo pathway and its nuclear effector Yap regulate organ size and cancer formation. While many modulators of Hippo activity have been identified, little is known about the Yap target genes that mediate these growth effects. Here, we show that yap -/- mutant zebrafish exhibit defects in hepatic progenitor potential and liver growth due to impaired glucose transport and nucleotide biosynthesis. Transcriptomic and metabolomic analyses reveal that Yap regulates expression of glucose transporter glut1, causing decreased glucose uptake and use for nucleotide biosynthesis in yap -/- mutants, and impaired glucose tolerance in adults. Nucleotide supplementation improves Yap deficiency phenotypes, indicating functional importance of glucose-fueled nucleotide biosynthesis. Yap-regulated glut1 expression and glucose uptake are conserved in mammals, suggesting that stimulation of anabolic glucose metabolism is an evolutionarily conserved mechanism by which the Hippo pathway controls organ growth. Together, our results reveal a central role for Hippo signaling in glucose metabolic homeostasis.


Assuntos
Glucose/metabolismo , Fígado/embriologia , Nucleotídeos/biossíntese , Transdução de Sinais/fisiologia , Transativadores/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Animais , Glucose/genética , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Camundongos , Nucleotídeos/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transativadores/genética , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
20.
Cell ; 175(1): 101-116.e25, 2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30220459

RESUMO

IDH1 mutations are common in low-grade gliomas and secondary glioblastomas and cause overproduction of (R)-2HG. (R)-2HG modulates the activity of many enzymes, including some that are linked to transformation and some that are probably bystanders. Although prior work on (R)-2HG targets focused on 2OG-dependent dioxygenases, we found that (R)-2HG potently inhibits the 2OG-dependent transaminases BCAT1 and BCAT2, likely as a bystander effect, thereby decreasing glutamate levels and increasing dependence on glutaminase for the biosynthesis of glutamate and one of its products, glutathione. Inhibiting glutaminase specifically sensitized IDH mutant glioma cells to oxidative stress in vitro and to radiation in vitro and in vivo. These findings highlight the complementary roles for BCATs and glutaminase in glutamate biosynthesis, explain the sensitivity of IDH mutant cells to glutaminase inhibitors, and suggest a strategy for maximizing the effectiveness of such inhibitors against IDH mutant gliomas.


Assuntos
Glioma/metabolismo , Ácido Glutâmico/biossíntese , Transaminases/fisiologia , Linhagem Celular Tumoral , Glioma/fisiopatologia , Ácido Glutâmico/efeitos dos fármacos , Glutaratos/metabolismo , Glutaratos/farmacologia , Homeostase/efeitos dos fármacos , Humanos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/fisiologia , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/fisiologia , Mutação , Oxirredução/efeitos dos fármacos , Proteínas da Gravidez/genética , Proteínas da Gravidez/fisiologia , Transaminases/antagonistas & inibidores , Transaminases/genética
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