| Literature DB >> 31813825 |
Claire L Bensard1, Dona R Wisidagama2, Kristofor A Olson1, Jordan A Berg1, Nathan M Krah2, John C Schell1, Sara M Nowinski1, Sarah Fogarty1, Alex J Bott1, Peng Wei1, Katja K Dove1, Jason M Tanner1, Vanja Panic1, Ahmad Cluntun1, Sandra Lettlova1, Christian S Earl1, David F Namnath1, Karina Vázquez-Arreguín3, Claudio J Villanueva1, Dean Tantin3, L Charles Murtaugh2, Kimberley J Evason4, Gregory S Ducker1, Carl S Thummel5, Jared Rutter6.
Abstract
Although metabolic adaptations have been demonstrated to be essential for tumor cell proliferation, the metabolic underpinnings of tumor initiation are poorly understood. We found that the earliest stages of colorectal cancer (CRC) initiation are marked by a glycolytic metabolic signature, including downregulation of the mitochondrial pyruvate carrier (MPC), which couples glycolysis and glucose oxidation through mitochondrial pyruvate import. Genetic studies in Drosophila suggest that this downregulation is required because hyperplasia caused by loss of the Apc or Notch tumor suppressors in intestinal stem cells can be completely blocked by MPC overexpression. Moreover, in two distinct CRC mouse models, loss of Mpc1 prior to a tumorigenic stimulus doubled the frequency of adenoma formation and produced higher grade tumors. MPC loss was associated with a glycolytic metabolic phenotype and increased expression of stem cell markers. These data suggest that changes in cellular pyruvate metabolism are necessary and sufficient to promote cancer initiation.Entities:
Keywords: cancer metabolism; carbohydrate metabolism; colon cancer; mitochondria; pyruvate metabolism; stem cell metabolism; tumor initiation
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Year: 2019 PMID： 31813825 PMCID： PMC7004878 DOI： 10.1016/j.cmet.2019.11.002
Source DB: PubMed Journal: Cell Metab ISSN： 1550-4131 Impact factor: 27.287