Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer
Open accessAbstract
Much of the mechanism by which Wnt signaling drives proliferation during oncogenesis is attributed to its regulation of the cell cycle. Here, we show how Wnt/β-catenin signaling directs another hallmark of tumorigenesis, namely Warburg metabolism. Using biochemical assays and fluorescence lifetime imaging microscopy (FLIM) to probe metabolism in vitro and in living tumors, we observe that interference with Wnt signaling in colon cancer cells reduces glycolytic metabolism and results in small, poorly perfused tumors. We identify pyruvate dehydrogenase kinase 1 (PDK1) as an important direct target within a larger gene program for metabolism. PDK1 inhibits pyruvate flux to mitochondrial respiration and a rescue of its expression in Wnt-inhibited cancer cells rescues glycolysis as well as vessel growth in the tumor microenvironment. Thus, we identify an important mechanism by which Wnt-driven Warburg metabolism directs the use of glucose for cancer cell proliferation and links it to vessel delivery of oxygen and nutrients.
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TCF/β-catenin signaling upregulates MCT1 and PDK1 transcription.
“In addition to c-myc, TCF/β-catenin signaling has also been shown to upregulate MCT1 and PDK1 transcription (Pate et al., 2014).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Pate et al., 2014
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- Authors
- Pate, K. T., Stringari, C., Sprowl‐Tanio, S., Wang, K., TeSlaa, T., Hoverter, N. P., McQuade, M. M., Garner, C., Digman, M. A., Teitell, M. A., Edwards, R. A., Gratton, E., & Waterman, M. L.
- Affiliations
- University of California, Irvine (US)
- University of California, Los Angeles (US)
- Corresponding author
- Waterman, Marian L
- ORCID
- Venue
- The EMBO Journal
- Published
- 2014-05-13
- Volume
- 33
- Issue
- 13
- Pages
- 1454-1473
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC4194089
- OpenAlex
- W2124000950
- Cited by
- 459
- References
- 85
- Citations by year
- 2026: 24 · 2025: 32 · 2024: 46 · 2023: 45 · 2022: 58 · 2021: 47 · 2020: 41 · 2019: 33 · 2018: 32 · 2017: 38 · 2016: 36 · 2015: 18 · 2014: 9
- FWCI
- 10.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- NIH (CA096878, CA108697, P30CA062203, P41‐RRO3155, P41 GM103540, P50‐GM076516)
- NIH NRSA (R01GM073981, P01GM081621, U01 AA021838, T32GM007185, R01CA90571, R01CA156674)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- Wnt/β-catenin signaling, colon cancer, Warburg effect, glycolysis, angiogenesis, pyruvate dehydrogenase kinase 1, cancer metabolism, tumor microenvironment, mitochondrial respiration, glucose metabolism, tumor perfusion
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Animals, Colonic Neoplasms, Glucose, Glycolysis, Humans, Mitochondria, Neoplasm Proteins, Neovascularization, Pathologic, Oxygen Consumption, Protein Serine-Threonine Kinases, Cell Line, Tumor, Mice, Tumor Microenvironment, Wnt Signaling Pathway
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