See also: CB Thompson (July 2014)
Wnt signaling directs a metabolic program of glycolysis and angiogenesis in colon cancer
Article first published online: 13 MAY 2014
© 2014 The Authors
The EMBO Journal
Volume 33, Issue 13, pages 1454–1473, 1 July 2014
How to Cite
The EMBO Journal (2014) 33: 1454–1473
- Issue published online: 1 JUL 2014
- Article first published online: 13 MAY 2014
- Manuscript Accepted: 31 MAR 2014
- Manuscript Received: 27 MAR 2014
- NIH. Grant Numbers: CA096878, CA108697, P30CA062203, P41-RRO3155, P41 GM103540, P50-GM076516
- NIH NRSA. Grant Numbers: R01GM073981, P01GM081621, U01 AA021838, T32GM007185, R01CA90571, R01CA156674
- colon cancer;
- fluorescence lifetime imaging;
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.
Waterman and colleagues functionally characterize PDK1 as crucial contributor toward Wnt-dependent metabolic and angiogenic transformations during colon cancer progression.
- Discover oncogenic Wnt signaling as driver of glycolytic metabolism and angiogenesis.
- Identify PDK1 as direct, executing Wnt target.
- Develop in vivo FLIM to image metabolic adaptations in living, perfused tumors.