title: 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.
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Schell
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA.
authors.forename: Kristofor A
authors.initials: KA
authors.lastname: Olson
authors.affiliation: Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX 75390-8502, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Hawkins
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Van Vranken
authors.affiliation: Cell Signaling Technology, Inc., Danvers, MA 01923, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Xie
authors.affiliation: Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX 75390-8502, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Egnatchik
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA.
authors.forename: Espen G
authors.initials: EG
authors.lastname: Earl
authors.affiliation: Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX 75390-8502, USA.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5650, USA. Electronic address: rutter@biochem.utah.edu.
authors.forename: Jared
authors.initials: J
authors.lastname: Rutter
mesh_terms: D000818:Animals; D027321:Anion Transport Proteins / Q000378:metabolism*; D049109:Cell Proliferation; D003110:Colonic Neoplasms; D006019:Glycolysis; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters; D009368:Neoplasm Transplantation; D010084:Oxidation-Reduction
chemical_list: D027321:Anion Transport Proteins; C573718:MPC1 protein, human; C000595572:MPC2 protein, human; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D027501:Monocarboxylic Acid Transporters