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Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer
Author(s) -
Pate Kira T,
Stringari Chiara,
SprowlTanio Stephanie,
Wang Kehui,
TeSlaa Tara,
Hoverter Nate P,
McQuade Miriam M,
Garner Chad,
Digman Michelle A,
Teitell Michael A,
Edwards Robert A,
Gratton Enrico,
Waterman Marian L
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201488598
Subject(s) - warburg effect , wnt signaling pathway , biology , carcinogenesis , glycolysis , microbiology and biotechnology , cancer cell , angiogenesis , cancer research , cell growth , signal transduction , cancer , biochemistry , metabolism , genetics
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 ( PDK 1) as an important direct target within a larger gene program for metabolism. PDK 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.