Glucose Deprivation Contributes to the Development of KRAS Pathway Mutations in Tumor Cells
Open accessAbstract
Desperately Seeking Glucose: Mutations in oncogenes and tumor suppressor genes allow cancer cells to outgrow their neighboring healthy cells. What microenvironmental conditions provide a selective growth advantage to these cells? Yun et al. (p. 1555 , published online 6 August) identify low glucose availability as a microenvironmental factor driving the acquisition of KRAS oncogenic mutations that allow cancer cells to survive and grow. In genetically matched colorectal cancer cells that differed only in the mutational status of the KRAS oncogene, mutant cells selectively overexpressed glucose transporter-1 and exhibited enhanced glucose uptake and glycolysis. When cells with wild-type KRAS were placed in a low-glucose environment, very few cells survived but most of the survivors expressed high levels of glucose transporter-1, and a small percentage of the survivors had acquired new KRAS mutations. Thus, glucose deprivation may help to drive the acquisition of cell growth–promoting oncogenic mutations during tumor development.
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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 [30]
Mutant KRAS or BRAF helps drive the Warburg effect partly by increasing GLUT1.
“Oncogenic KRAS or BRAF mutations contribute to the Warburg effect, in part by upregulating GLUT1 (REF46).”
From Targeting cancer vulnerabilities with high-dose vitamin C (2019) · cites this paper as [46]
Most cancers have highly effective upregulated, insulin-independent glucose uptake mechanisms and therefore may not derive a further growth advantage from hyperglycemia.
“Direct data concerning dose-response characteristics of cancers to glucose are sparse, but it is relevant that most cancers have highly effective upregulated, insulin-independent glucose uptake mechanisms (67) and therefore may not derive a further growth advantage from hyperglycemia.”
From Diabetes and Cancer (2010) · cites this paper as [67]
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- Authors
- Yun, J., Rago, C., Cheong, I., Pagliarini, R., Angenendt, P., Rajagopalan, H., Schmidt, K., Willson, J. K. V., Markowitz, S., Zhou, S., Diaz, L. A., Velculescu, V. E., Lengauer, C., Kinzler, K. W., Vogelstein, B., & Papadopoulos, N.
- Affiliations
- Howard Hughes Medical Institute (US)
- The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
- Harold C. Simmons Comprehensive Cancer Center (US)
- Corresponding author
- Rajagopalan, Harith
- Vogelstein, Bert
- ORCID
- Venue
- Science
- Published
- 2009-09-18
- Volume
- 325
- Issue
- 5947
- Pages
- 1555-1559
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2820374
- OpenAlex
- W1970766774
- Cited by
- 914
- References
- 42
- Citations by year
- 2026: 21 · 2025: 39 · 2024: 43 · 2023: 47 · 2022: 48 · 2021: 60 · 2020: 70 · 2019: 75 · 2018: 61 · 2017: 60 · 2016: 63 · 2015: 51 · 2014: 87 · 2013: 48 · 2012: 61
- FWCI
- 15.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA43460, R37CA043460, P50CA062924, CA 62924)
- 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 Genomics and Diagnostics
- Keywords
- glucose deprivation, KRAS mutation, BRAF mutation, GLUT1, glucose transporter 1, colorectal cancer cell lines, tumor progression, glycolysis, glucose uptake, 3-bromopyruvate, transcriptome
- MeSH terms
- Animals, Glucose, Glycolysis, Humans, Mice, Nude, Mutation, Neoplasm Transplantation, Pyruvates, Genes, ras, Transplantation, Heterologous, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Gene Targeting, Lactic Acid, Oligonucleotide Array Sequence Analysis, Cell Line, Tumor, Proto-Oncogene Proteins B-raf, Cell Proliferation, Glucose Transporter Type 1, Mice
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