TY - JOUR
T1 - A role for the mitochondrial pyruvate carrier as a repressor of the warburg effect and colon cancer cell growth
AU - Schell, John C.
AU - Olson, Kristofor A.
AU - Jiang, Lei
AU - Hawkins, Amy J.
AU - VanVranken, Jonathan G.
AU - Xie, Jianxin
AU - Egnatchik, Robert A.
AU - Earl, Espen G.
AU - DeBerardinis, Ralph J.
AU - Rutter, Jared
N1 - Funding Information:
The authors would like to acknowledge the following individuals for their contribution to this work: James Marvin for his consultation and flow cytometry training and Chris Leukel for lively discussion regarding flow cytometry. We thank Janet Bassett and our fellow students in the MD/PhD Program including Dr. Jess Maddox, Joe Cho, Jon Downie, and Alex Keefe. We thank Dr. Dave Jones for reviewing this manuscript. We thank Drs. Dean Tantin, Sue Hammoud, Don Ayer, Janet Shaw, Sihem Boudina, James Cox, Jerry Kaplan, Janet Lindsley, Amnon Schlegel, Adam Frost, Rich Dorsky, Jody Rosenblatt, Ed Levine, Joe Yost, Charlie Murtaugh, Carl Thummel, and members of the Rutter Lab for discussion and insight. We thank Drs. Nikolaos Diakos, Stavros Drakos, and Dean Li for human heart tissue samples and the Huntsman Cancer Institute Biorepository for the human colon tissue samples. We thank the Metabolic Phenotyping Core for their expertise and services. This project was supported by the Nora Eccles Treadwell Foundation (to J.R.) and NIH R01 GM094232 (to J.R.), NIH Developmental Biology Training Grant 5T32HD07491 (to J.C.S.), NIH Hematology Training Grant 5T32DK007115-40 (to K.A.O.), NIH R01 CA157996 (to R.J.D.), CPRIT: RP130272 (to R.J.D.); NCI P30CA042014 (to HCI Biorepository), and NCRR 1S10RR026802-01 (to Utah Flow Cytometry Core). A.J.H. was supported by an American Cancer Society-Daiichi Sankyo, Inc. Postdoctoral Fellowship, grant number PF-13-363-01-TBE.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2014.09.026
DO - 10.1016/j.molcel.2014.09.026
M3 - Article
C2 - 25458841
AN - SCOPUS:84922445353
VL - 56
SP - 400
EP - 413
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 3
ER -