Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes
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Background: Activating KRAS mutations are important for cancer initiation and progression; and have recently been shown to cause primary resistance to therapies targeting the epidermal growth factor receptor. Therefore, strategies are currently in development to overcome treatment resistance due to oncogenic KRAS. The hypoxia-inducible factors-1α and -2α (HIF-1α and HIF-2α) are activated in cancer due to dysregulated ras signaling. Methods: To understand the individual and combined roles of HIF-1α and HIF-2α in cancer metabolism and oncogenic KRAS signaling, we used targeted homologous recombination to disrupt the oncogenic KRAS, HIF-1α, and HIF-2α gene loci in HCT116 colon cancer cells to generate isogenic HCT116 WT KRAS, HCT116 HIF-1α-/-, HCT116 HIF-2α-/-, and HCT116 HIF-1α-/-HIF-2α-/- cell lines. Results: Global gene expression analyses of these cell lines reveal that HIF-1α and HIF-2α work together to modulate cancer metabolism and regulate genes signature overlapping with oncogenic KRAS. Cancer cells with disruption of both HIF-1α and HIF-2α or oncogenic KRAS showed decreased aerobic respiration and ATP production, with increased ROS generation. Conclusion: Our findings suggest novel strategies for treating tumors with oncogenic KRAS mutations.
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Oncogenic KRAS upregulates PFK1, ENO1, and LDHA, promoting glycolytic flux and production of intermediates that can enter anabolic pathways.
“Oncogenic KRAS also upregulates expression of other key glycolytic enzymes, such as PFK1, ENO1, and LDHA28,31–33, thereby promoting glycolytic flux and enabling the production of glycolytic intermediates that can be shunted into other anabolic pathways (Fig 2).”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [33]
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- Authors
- Chun, S. Y., Johnson, C., Washburn, J. G., Cruz-Correa, M. R., Dang, D. T., & Dang, L. H.
- Affiliations
- University of Michigan (US)
- University of Puerto Rico System (PR)
- University of Florida (US)
- Corresponding author
- Dang, Long H
- Venue
- Molecular Cancer
- Published
- 2010-11-13
- Volume
- 9
- Issue
- 1
- Pages
- 293-293
- ISSN
- 1476-4598 (ISSN-L)
- PMC
- PMC2999617
- OpenAlex
- W2107951449
- Cited by
- 109
- References
- 39
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 8 · 2023: 6 · 2022: 14 · 2021: 12 · 2020: 8 · 2019: 4 · 2018: 3 · 2017: 3 · 2016: 6 · 2015: 4 · 2014: 13 · 2013: 8 · 2012: 3
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Cancer (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Pfizer
- National Comprehensive Cancer Network
- National Institutes of Health
- University of Michigan Comprehensive Cancer Center
- National Cancer Institute (R21CA115809, K22CA111897)
- 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 › Molecular Biology › Kruppel-like factors research
- Keywords
- oncogenic KRAS, HIF-1α, HIF-2α, hypoxia-inducible factor, colon cancer, mitochondrial metabolism, aerobic respiration, reactive oxygen species, ATP production, KRAS mutation, isogenic cell lines, HCT116 cells, cancer metabolism
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Adenosine Triphosphate, Colonic Neoplasms, Humans, Mitochondria, Oxygen Consumption, Proto-Oncogene Proteins, Blotting, Western, Proto-Oncogene Proteins p21(ras), Mutagenesis, Site-Directed, Reactive Oxygen Species, ras Proteins, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, HCT116 Cells, Cell Line, Tumor, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit
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