A Role for the Mitochondrial Pyruvate Carrier as a Repressor of the Warburg Effect and Colon Cancer Cell Growth

• Published in: Molecular cell Vol. 56; no. 3; pp. 400 - 413
• Main Authors: Schell, John C., Olson, Kristofor A., Jiang, Lei, Hawkins, Amy J., Van Vranken, Jonathan G., Xie, Jianxin, Egnatchik, Robert A., Earl, Espen G., DeBerardinis, Ralph J., Rutter, Jared
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.11.2014
• Subjects: agar; Animals; Anion Transport Proteins - metabolism; cell growth; Cell Proliferation; Colonic Neoplasms; colorectal neoplasms; genes; Glycolysis; HEK293 Cells; HT29 Cells; Humans; Mice, Nude; mitochondria; Mitochondria - metabolism; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Proteins - metabolism; neoplasm cells; Neoplasm Transplantation; oxidation; Oxidation-Reduction; prognosis; pyruvic acid; stem cells
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2014.09.026

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. [Display omitted] •MPC1 downregulation/deletion in many cancers correlates with poor survival•The MPC complex is a node by which cancer cells regulate pyruvate metabolism•Re-expressing MPC1+2 in colon cancer cells reduces growth in 3D and xenografts•The deleterious effects of MPC re-expression manifest in the stem cell compartment Cancer cells enforce the metabolic perturbation known as the Warburg effect by reducing pyruvate utilization via loss of the mitochondrial pyruvate carrier (MPC). Re-expression of the MPC restores mitochondrial pyruvate oxidation and limits colon cancer cell growth in anchorage-independent culture and xenografts due to defects in the proliferating cell population.