Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth

Daniela Gaglio, Christian M. Metallo, Paulo A. Gameiro, Karsten Hiller, Lara Sala Danna, Chiara Balestrieri, Lilia Alberghina, Gregory Stephanopoulos, Ferdinando Chiaradonna

Research output: Contribution to journalArticle

250 Citations (Scopus)

Abstract

Oncogenes such as K-ras mediate cellular and metabolic transformation during tumorigenesis. To analyze K-Ras-dependent metabolic alterations, we employed 13 C metabolic flux analysis (MFA), non-targeted tracer fate detection (NTFD) of 15 N-labeled glutamine, and transcriptomic profiling in mouse fibroblast and human carcinoma cell lines. Stable isotope-labeled glucose and glutamine tracers and computational determination of intracellular fluxes indicated that cells expressing oncogenic K-Ras exhibited enhanced glycolytic activity, decreased oxidative flux through the tricarboxylic acid (TCA) cycle, and increased utilization of glutamine for anabolic synthesis. Surprisingly, a non-canonical labeling of TCA cycle-associated metabolites was detected in both transformed cell lines. Transcriptional profiling detected elevated expression of several genes associated with glycolysis, glutamine metabolism, and nucleotide biosynthesis upon transformation with oncogenic K-Ras. Chemical perturbation of enzymes along these pathways further supports the decoupling of glycolysis and TCA metabolism, with glutamine supplying increased carbon to drive the TCA cycle. These results provide evidence for a role of oncogenic K-Ras in the metabolic reprogramming of cancer cells. [-] [-].

Original languageEnglish
Article number523
JournalMolecular Systems Biology
Volume7
DOIs
Publication statusPublished - 2011

Fingerprint

Cell growth
Glutamine
Glucose
Metabolism
glutamine
cell growth
Cancer
Cells
Citric Acid Cycle
tricarboxylic acid cycle
Glycolysis
glucose
metabolism
Cell
Growth
Fluxes
Profiling
Cycle
glycolysis
Neoplasms

Keywords

  • cancer
  • metabolic flux analysis
  • metabolism
  • Ras
  • transcriptional analysis

ASJC Scopus subject areas

  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Computational Theory and Mathematics
  • Information Systems
  • Applied Mathematics

Cite this

Gaglio, D., Metallo, C. M., Gameiro, P. A., Hiller, K., Danna, L. S., Balestrieri, C., ... Chiaradonna, F. (2011). Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. Molecular Systems Biology, 7, [523]. https://doi.org/10.1038/msb.2011.56

Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. / Gaglio, Daniela; Metallo, Christian M.; Gameiro, Paulo A.; Hiller, Karsten; Danna, Lara Sala; Balestrieri, Chiara; Alberghina, Lilia; Stephanopoulos, Gregory; Chiaradonna, Ferdinando.

In: Molecular Systems Biology, Vol. 7, 523, 2011.

Research output: Contribution to journalArticle

Gaglio, D, Metallo, CM, Gameiro, PA, Hiller, K, Danna, LS, Balestrieri, C, Alberghina, L, Stephanopoulos, G & Chiaradonna, F 2011, 'Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth', Molecular Systems Biology, vol. 7, 523. https://doi.org/10.1038/msb.2011.56
Gaglio, Daniela ; Metallo, Christian M. ; Gameiro, Paulo A. ; Hiller, Karsten ; Danna, Lara Sala ; Balestrieri, Chiara ; Alberghina, Lilia ; Stephanopoulos, Gregory ; Chiaradonna, Ferdinando. / Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth. In: Molecular Systems Biology. 2011 ; Vol. 7.
@article{cab8ca89732c47dd9604090a96b9b585,
title = "Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth",
abstract = "Oncogenes such as K-ras mediate cellular and metabolic transformation during tumorigenesis. To analyze K-Ras-dependent metabolic alterations, we employed 13 C metabolic flux analysis (MFA), non-targeted tracer fate detection (NTFD) of 15 N-labeled glutamine, and transcriptomic profiling in mouse fibroblast and human carcinoma cell lines. Stable isotope-labeled glucose and glutamine tracers and computational determination of intracellular fluxes indicated that cells expressing oncogenic K-Ras exhibited enhanced glycolytic activity, decreased oxidative flux through the tricarboxylic acid (TCA) cycle, and increased utilization of glutamine for anabolic synthesis. Surprisingly, a non-canonical labeling of TCA cycle-associated metabolites was detected in both transformed cell lines. Transcriptional profiling detected elevated expression of several genes associated with glycolysis, glutamine metabolism, and nucleotide biosynthesis upon transformation with oncogenic K-Ras. Chemical perturbation of enzymes along these pathways further supports the decoupling of glycolysis and TCA metabolism, with glutamine supplying increased carbon to drive the TCA cycle. These results provide evidence for a role of oncogenic K-Ras in the metabolic reprogramming of cancer cells. [-] [-].",
keywords = "cancer, metabolic flux analysis, metabolism, Ras, transcriptional analysis",
author = "Daniela Gaglio and Metallo, {Christian M.} and Gameiro, {Paulo A.} and Karsten Hiller and Danna, {Lara Sala} and Chiara Balestrieri and Lilia Alberghina and Gregory Stephanopoulos and Ferdinando Chiaradonna",
year = "2011",
doi = "10.1038/msb.2011.56",
language = "English",
volume = "7",
journal = "Molecular Systems Biology",
issn = "1744-4292",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Oncogenic K-Ras decouples glucose and glutamine metabolism to support cancer cell growth

AU - Gaglio, Daniela

AU - Metallo, Christian M.

AU - Gameiro, Paulo A.

AU - Hiller, Karsten

AU - Danna, Lara Sala

AU - Balestrieri, Chiara

AU - Alberghina, Lilia

AU - Stephanopoulos, Gregory

AU - Chiaradonna, Ferdinando

PY - 2011

Y1 - 2011

N2 - Oncogenes such as K-ras mediate cellular and metabolic transformation during tumorigenesis. To analyze K-Ras-dependent metabolic alterations, we employed 13 C metabolic flux analysis (MFA), non-targeted tracer fate detection (NTFD) of 15 N-labeled glutamine, and transcriptomic profiling in mouse fibroblast and human carcinoma cell lines. Stable isotope-labeled glucose and glutamine tracers and computational determination of intracellular fluxes indicated that cells expressing oncogenic K-Ras exhibited enhanced glycolytic activity, decreased oxidative flux through the tricarboxylic acid (TCA) cycle, and increased utilization of glutamine for anabolic synthesis. Surprisingly, a non-canonical labeling of TCA cycle-associated metabolites was detected in both transformed cell lines. Transcriptional profiling detected elevated expression of several genes associated with glycolysis, glutamine metabolism, and nucleotide biosynthesis upon transformation with oncogenic K-Ras. Chemical perturbation of enzymes along these pathways further supports the decoupling of glycolysis and TCA metabolism, with glutamine supplying increased carbon to drive the TCA cycle. These results provide evidence for a role of oncogenic K-Ras in the metabolic reprogramming of cancer cells. [-] [-].

AB - Oncogenes such as K-ras mediate cellular and metabolic transformation during tumorigenesis. To analyze K-Ras-dependent metabolic alterations, we employed 13 C metabolic flux analysis (MFA), non-targeted tracer fate detection (NTFD) of 15 N-labeled glutamine, and transcriptomic profiling in mouse fibroblast and human carcinoma cell lines. Stable isotope-labeled glucose and glutamine tracers and computational determination of intracellular fluxes indicated that cells expressing oncogenic K-Ras exhibited enhanced glycolytic activity, decreased oxidative flux through the tricarboxylic acid (TCA) cycle, and increased utilization of glutamine for anabolic synthesis. Surprisingly, a non-canonical labeling of TCA cycle-associated metabolites was detected in both transformed cell lines. Transcriptional profiling detected elevated expression of several genes associated with glycolysis, glutamine metabolism, and nucleotide biosynthesis upon transformation with oncogenic K-Ras. Chemical perturbation of enzymes along these pathways further supports the decoupling of glycolysis and TCA metabolism, with glutamine supplying increased carbon to drive the TCA cycle. These results provide evidence for a role of oncogenic K-Ras in the metabolic reprogramming of cancer cells. [-] [-].

KW - cancer

KW - metabolic flux analysis

KW - metabolism

KW - Ras

KW - transcriptional analysis

UR - http://www.scopus.com/inward/record.url?scp=80051866908&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80051866908&partnerID=8YFLogxK

U2 - 10.1038/msb.2011.56

DO - 10.1038/msb.2011.56

M3 - Article

C2 - 21847114

AN - SCOPUS:80051866908

VL - 7

JO - Molecular Systems Biology

JF - Molecular Systems Biology

SN - 1744-4292

M1 - 523

ER -