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A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth.

Abstract
Cancer cells are typically subject to profound metabolic alterations, including the Warburg effect wherein cancer cells oxidize a decreased fraction of the pyruvate generated from glycolysis. We show herein that the mitochondrial pyruvate carrier (MPC), composed of the products of the MPC1 and MPC2 genes, modulates fractional pyruvate oxidation. MPC1 is deleted or underexpressed in multiple cancers and correlates with poor prognosis. Cancer cells re-expressing MPC1 and MPC2 display increased mitochondrial pyruvate oxidation, with no changes in cell growth in adherent culture. MPC re-expression exerted profound effects in anchorage-independent growth conditions, however, including impaired colony formation in soft agar, spheroid formation, and xenograft growth. We also observed a decrease in markers of stemness and traced the growth effects of MPC expression to the stem cell compartment. We propose that reduced MPC activity is an important aspect of cancer metabolism, perhaps through altering the maintenance and fate of stem cells.
AuthorsJohn C Schell, Kristofor A Olson, Lei Jiang, Amy J Hawkins, Jonathan G Van Vranken, Jianxin Xie, Robert A Egnatchik, Espen G Earl, Ralph J DeBerardinis, Jared Rutter
JournalMolecular cell (Mol Cell) Vol. 56 Issue 3 Pg. 400-413 (Nov 06 2014) ISSN: 1097-4164 [Electronic] United States
PMID25458841 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 Elsevier Inc. All rights reserved.
Chemical References
  • Anion Transport Proteins
  • MPC1 protein, human
  • MPC2 protein, human
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • Monocarboxylic Acid Transporters
Topics
  • Animals
  • Anion Transport Proteins (metabolism)
  • Cell Proliferation
  • Colonic Neoplasms
  • Glycolysis
  • HEK293 Cells
  • HT29 Cells
  • Humans
  • Mice, Nude
  • Mitochondria (metabolism)
  • Mitochondrial Membrane Transport Proteins (metabolism)
  • Mitochondrial Proteins (metabolism)
  • Monocarboxylic Acid Transporters
  • Neoplasm Transplantation
  • Oxidation-Reduction

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