Oncogenic K‐Ras decouples glucose and glutamine metabolism to support cancer cell growth
Open accessAbstract
Oncogenes such as K-ras mediate cellular and metabolic transformation during tumorigenesis. To analyze K-Ras-dependent metabolic alterations, we employed ¹³C metabolic flux analysis (MFA), non-targeted tracer fate detection (NTFD) of ¹⁵N-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.
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Mutant KRAS upregulates GLUT1 to increase glucose uptake and induces HK1 and HK2 to increase glycolytic activity.
“Gene expression and metabolic flux analyses have shown that it upregulates the expression of the GLUT1 glucose transporter to promote glucose uptake by cells, as well as inducing expression of hexokinase 1 and 2 (HK1 and HK2) rate-limiting enzymes of glycolysis, to increase glycolytic activity27–30 (Fig. 2a).”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [27]
Oncogenic KRAS elevates expression of enzymes involved in glutaminolysis.
“Oncogenic KRAS elevates the gene expression of enzymes involved in glutaminolysis27.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [27]
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- Authors
- Gaglio, D., Metallo, C. M., Gameiro, P. A., Hiller, K., Danna, L. S., Balestrieri, C., Alberghina, L., Stephanopoulos, G., & Chiaradonna, F.
- Affiliations
- Massachusetts Institute of Technology (US)
- University of Milano-Bicocca (IT)
- Corresponding author
- Alberghina, Lilia
- Stephanopoulos, Gregory
- ORCID
- Venue
- Molecular Systems Biology
- Published
- 2011-08-16
- Volume
- 7
- Issue
- 1
- Pages
- 523-523
- ISSN
- 1744-4292 (ISSN-L)
- PMC
- PMC3202795
- OpenAlex
- W2141517721
- Cited by
- 492
- References
- 63
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 37 · 2023: 28 · 2022: 36 · 2021: 40 · 2020: 41 · 2019: 41 · 2018: 43 · 2017: 31 · 2016: 41 · 2015: 38 · 2014: 31 · 2013: 32 · 2012: 22
- FWCI
- 9.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Systems Biology (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion)
- Funders
- American Cancer Society
- Ministero dell’Istruzione, dell’Università e della Ricerca
- National Institutes of Health (MDA-MB-231)
- National Cancer Institute (R01CA160458)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK075850)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- oncogenic KRAS, tumor metabolic reprogramming, glucose metabolism, glutamine metabolism, glycolysis, TCA cycle, metabolic flux analysis, 13C metabolic flux analysis, nucleotide synthesis, tumor cell proliferation, oncogenic transformation
- MeSH terms
- Animals, Cell Line, Transformed, Cell Transformation, Neoplastic, Citric Acid Cycle, Fibroblasts, Flow Cytometry, Glucose, Glutamine, Glycolysis, Humans, Isotope Labeling, Gas Chromatography-Mass Spectrometry, Neoplasms, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, NIH 3T3 Cells, Cell Line, Tumor, Cell Proliferation, Mice
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