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Mol Cell. 2015 Nov 19;60(4):571-83. doi: 10.1016/j.molcel.2015.09.025. Epub 2015 Oct 17.

PEPCK Coordinates the Regulation of Central Carbon Metabolism to Promote Cancer Cell Growth.

Author information

1
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.
2
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
3
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Pathology, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA.
4
Department of Pathology, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA.
5
Children's Medical Center Research Institute at the University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
6
Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
7
University of California, Los Angeles School of Medicine, Los Angeles, CA 90095, USA; Los Angeles Biomedical Research Institute (LA BioMed) and SIDMAP, Torrance, CA 90502 USA.
8
Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
9
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
10
Department of Medicine, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
11
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pathology, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA. Electronic address: geoffrey.girnun@stonybrookmedicine.edu.

Abstract

Phosphoenolpyruvate carboxykinase (PEPCK) is well known for its role in gluconeogenesis. However, PEPCK is also a key regulator of TCA cycle flux. The TCA cycle integrates glucose, amino acid, and lipid metabolism depending on cellular needs. In addition, biosynthetic pathways crucial to tumor growth require the TCA cycle for the processing of glucose and glutamine derived carbons. We show here an unexpected role for PEPCK in promoting cancer cell proliferation in vitro and in vivo by increasing glucose and glutamine utilization toward anabolic metabolism. Unexpectedly, PEPCK also increased the synthesis of ribose from non-carbohydrate sources, such as glutamine, a phenomenon not previously described. Finally, we show that the effects of PEPCK on glucose metabolism and cell proliferation are in part mediated via activation of mTORC1. Taken together, these data demonstrate a role for PEPCK that links metabolic flux and anabolic pathways to cancer cell proliferation.

PMID:
26481663
PMCID:
PMC4656111
DOI:
10.1016/j.molcel.2015.09.025
[Indexed for MEDLINE]
Free PMC Article

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