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

Mol Cell. 2014 Nov 6;56(3):400-13. doi: 10.1016/j.molcel.2014.09.026. Epub 2014 Oct 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Anion Transport Proteins
  • MPC1 protein, human
  • MPC2 protein, human
  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • Monocarboxylic Acid Transporters