Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer
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- Kira T Pate
- Department of Microbiology and Molecular Genetics University of California Irvine CA USA
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- Chiara Stringari
- Laboratory of Fluorescence Dynamics Department of Biomedical Engineering University of California Irvine CA USA
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- Stephanie Sprowl‐Tanio
- Department of Microbiology and Molecular Genetics University of California Irvine CA USA
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- Kehui Wang
- Department of Pathology and Laboratory Medicine University of California Irvine CA USA
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- Tara TeSlaa
- Departments of Pathology, Pediatrics, and Bioengineering David Geffen School of Medicine University of California Los Angeles CA USA
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- Nate P Hoverter
- Department of Microbiology and Molecular Genetics University of California Irvine CA USA
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- Miriam M McQuade
- Department of Microbiology and Molecular Genetics University of California Irvine CA USA
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- Chad Garner
- Department of Epidemiology University of California Irvine CA USA
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- Michelle A Digman
- Laboratory of Fluorescence Dynamics Department of Biomedical Engineering University of California Irvine CA USA
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- Michael A Teitell
- Departments of Pathology, Pediatrics, and Bioengineering David Geffen School of Medicine University of California Los Angeles CA USA
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- Robert A Edwards
- Department of Pathology and Laboratory Medicine University of California Irvine CA USA
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- Enrico Gratton
- Laboratory of Fluorescence Dynamics Department of Biomedical Engineering University of California Irvine CA USA
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- Marian L Waterman
- Department of Microbiology and Molecular Genetics University of California Irvine CA USA
説明
<jats:title>Abstract</jats:title><jats:p>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 (<jats:styled-content style="fixed-case">FLIM</jats:styled-content>) to probe metabolism <jats:italic>in vitro</jats:italic> 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 (<jats:styled-content style="fixed-case">PDK</jats:styled-content>1) as an important direct target within a larger gene program for metabolism. <jats:styled-content style="fixed-case">PDK</jats:styled-content>1 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.</jats:p>
収録刊行物
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- The EMBO Journal
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The EMBO Journal 33 (13), 1454-1473, 2014-05-13
Springer Science and Business Media LLC