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Myc-induced glutaminolysis bypasses HIF-driven glycolysis in hypoxic small cell lung carcinoma cells.

ABSTRACT: We previously demonstrated that small cell lung carcinoma (SCLC) cells lack HIF-2? protein expression, whereas HIF-1? in these cells is expressed at both acute and prolonged hypoxia. Here we show that low HIF2A expression correlates with high expression of MYC genes. Knockdown of HIF1A expression had no or limited effect on cell survival and growth in vitro. Unexpectedly, hypoxic ATP levels were not affected by HIF-1? knockdown and SCLC cell viability did not decrease upon glucose deprivation. In line with these in vitro data, xenograft tumor-take and growth were not significantly affected by repressed HIF1A expression. Glutamine withdrawal drastically decreased SCLC cell proliferation and increased cell death at normoxia and hypoxia in a HIF-independent fashion and the dependence on glutaminolysis was linked to amplification of either MYC or MYCL. Downregulation of GLS expression, regulating the first step of the glutaminolysis pathway, in MYC/MYCL overexpressing SCLC cells resulted in both impaired growth and increased cell death. Our results suggest that MYC/MYCL overexpression in SCLC cells overrides the need of HIF-1 activity in response to hypoxia by inducing glutaminolysis and lipogenesis. Targeting the glutaminolysis pathway might hence be a novel approach to selectively kill MYC amplified SCLC cells in vivo.

SUBMITTER: Munksgaard Thoren M

PROVIDER: S-EPMC5564742 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Myc-induced glutaminolysis bypasses HIF-driven glycolysis in hypoxic small cell lung carcinoma cells.

Munksgaard Thorén Matilda M Vaapil Marica M Staaf Johan J Planck Maria M Johansson Martin E ME Mohlin Sofie S Påhlman Sven S

Oncotarget 20170701 30

We previously demonstrated that small cell lung carcinoma (SCLC) cells lack HIF-2α protein expression, whereas HIF-1α in these cells is expressed at both acute and prolonged hypoxia. Here we show that low HIF2A expression correlates with high expression of MYC genes. Knockdown of HIF1A expression had no or limited effect on cell survival and growth in vitro. Unexpectedly, hypoxic ATP levels were not affected by HIF-1α knockdown and SCLC cell viability did not decrease upon glucose deprivation. I ...[more]

PMID: 28430666

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Project description:PurposeDeregulated Myc drives an oncogenic metabolic state, including pseudohypoxic glycolysis, adapted for the constitutive production of biomolecular precursors to feed rapid tumor cell growth. In glioblastoma, Myc facilitates renewal of the tumor-initiating cell reservoir contributing to tumor maintenance. We investigated whether targeting the Myc-driven metabolic state could be a selectively toxic therapeutic strategy for glioblastoma.Experimental designThe glycolytic dependency of Myc-driven glioblastoma was tested using (13)C metabolic flux analysis, glucose-limiting culture assays, and glycolysis inhibitors, including inhibitors of the NAD(+) salvage enzyme nicotinamide phosphoribosyl-transferase (NAMPT), in MYC and MYCN shRNA knockdown and lentivirus overexpression systems and in patient-derived glioblastoma tumorspheres with and without MYC/MYCN amplification. The in vivo efficacy of glycolyic inhibition was tested using NAMPT inhibitors in MYCN-amplified patient-derived glioblastoma orthotopic xenograft mouse models.ResultsEnforced Myc overexpression increased glucose flux and expression of glycolytic enzymes in glioblastoma cells. Myc and N-Myc knockdown and Myc overexpression systems demonstrated that Myc activity determined sensitivity and resistance to inhibition of glycolysis. Small-molecule inhibitors of glycolysis, particularly NAMPT inhibitors, were selectively toxic to MYC/MYCN-amplified patient-derived glioblastoma tumorspheres. NAMPT inhibitors were potently cytotoxic, inducing apoptosis and significantly extended the survival of mice bearing MYCN-amplified patient-derived glioblastoma orthotopic xenografts.ConclusionsMyc activation in glioblastoma generates a dependency on glycolysis and an addiction to metabolites required for glycolysis. Glycolytic inhibition via NAMPT inhibition represents a novel metabolically targeted therapeutic strategy for MYC or MYCN-amplified glioblastoma and potentially other cancers genetically driven by Myc. Clin Cancer Res; 22(17); 4452-65. ©2016 AACR.

Project description:Cancer cells use glucose and glutamine as the major sources of energy and precursor intermediates, and enhanced glycolysis and glutamimolysis are the major hallmarks of metabolic reprogramming in cancer. Oncogene activation and tumor suppressor gene inactivation alter multiple intracellular signaling pathways that affect glycolysis and glutaminolysis. N-Myc downstream regulated gene 2 (NDRG2) is a tumor suppressor gene inhibiting cancer growth, metastasis and invasion. However, the role and molecular mechanism of NDRG2 in cancer metabolism remains unclear. In this study, we discovered the role of the tumor suppressor gene NDRG2 in aerobic glycolysis and glutaminolysis of cancer cells. NDRG2 inhibited glucose consumption and lactate production, glutamine consumption and glutamate production in colorectal cancer cells. Analysis of glucose transporters and the catalytic enzymes involved in glycolysis revealed that glucose transporter 1 (GLUT1), hexokinase 2 (HK2), pyruvate kinase M2 isoform (PKM2) and lactate dehydrogenase A (LDHA) was significantly suppressed by NDRG2. Analysis of glutamine transporter and the catalytic enzymes involved in glutaminolysis revealed that glutamine transporter ASC amino-acid transporter 2 (ASCT2) and glutaminase 1 (GLS1) was also significantly suppressed by NDRG2. Transcription factor c-Myc mediated inhibition of glycolysis and glutaminolysis by NDRG2. More importantly, NDRG2 inhibited the expression of c-Myc by suppressing the expression of ?-catenin, which can transcriptionally activate C-MYC gene in nucleus. In addition, the growth and proliferation of colorectal cancer cells were suppressed significantly by NDRG2 through inhibition of glycolysis and glutaminolysis. Taken together, these findings indicate that NDRG2 functions as an essential regulator in glycolysis and glutaminolysis via repression of c-Myc, and acts as a suppressor of carcinogenesis through coordinately targeting glucose and glutamine transporter, multiple catalytic enzymes involved in glycolysis and glutaminolysis, which fuels the bioenergy and biomaterials needed for cancer proliferation and progress.

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Myc-induced glutaminolysis bypasses HIF-driven glycolysis in hypoxic small cell lung carcinoma cells.

Publications

Myc-induced glutaminolysis bypasses HIF-driven glycolysis in hypoxic small cell lung carcinoma cells.

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