Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer.
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.
Department of Microbiology and Molecular Genetics, University of California, Irvine, CA, USA.
Kira T
KT
Pate
Laboratory of Fluorescence Dynamics, Department of Biomedical Engineering, University of California, Irvine, CA, USA.
Chiara
C
Stringari
Department of Microbiology and Molecular Genetics, University of California, Irvine, CA, USA.
Stephanie
S
Sprowl-Tanio
Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA.
Kehui
K
Wang
Departments of Pathology, Pediatrics, and Bioengineering, David Geffen School of Medicine University of California, Los Angeles, CA, USA.
Tara
T
TeSlaa
Department of Microbiology and Molecular Genetics, University of California, Irvine, CA, USA.
Nate P
NP
Hoverter
Department of Microbiology and Molecular Genetics, University of California, Irvine, CA, USA.
Miriam M
MM
McQuade
Department of Epidemiology, University of California, Irvine, CA, USA.
Chad
C
Garner
Laboratory of Fluorescence Dynamics, Department of Biomedical Engineering, University of California, Irvine, CA, USA.
Michelle A
MA
Digman
Departments of Pathology, Pediatrics, and Bioengineering, David Geffen School of Medicine University of California, Los Angeles, CA, USA.
Michael A
MA
Teitell
Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, USA.
Robert A
RA
Edwards
Laboratory of Fluorescence Dynamics, Department of Biomedical Engineering, University of California, Irvine, CA, USA.
Enrico
E
Gratton
Department of Microbiology and Molecular Genetics, University of California, Irvine, CA, USA marian.waterman@uci.edu.
Marian L
ML
Waterman
D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010101:Oxygen Consumption / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D059016:Tumor Microenvironment; D060449:Wnt Signaling Pathway
D009363:Neoplasm Proteins; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases; D005947:Glucose
Wnt; angiogenesis; colon cancer; fluorescence lifetime imaging; metabolism