PEPCK Coordinates the Regulation of Central Carbon Metabolism to Promote Cancer Cell Growth.
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.
Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794, USA.
Emily D
ED
Montal
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Ruby
R
Dewi
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.
Kavita
K
Bhalla
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Lihui
L
Ou
Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Bor Jang
BJ
Hwang
Department of Pathology, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA.
Ashley E
AE
Ropell
Department of Pathology, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA.
Chris
C
Gordon
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.
Wan-Ju
WJ
Liu
Children's Medical Center Research Institute at the University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
Ralph J
RJ
DeBerardinis
Children's Medical Center Research Institute at the University of Texas Southwestern Medical Center, Dallas, TX 75390-8502, USA.
Jessica
J
Sudderth
Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
William
W
Twaddel
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.
Laszlo G
LG
Boros
Department of Pathology, Stony Brook University School of Medicine, Stony Brook, NY 11794, USA.
Kenneth R
KR
Shroyer
Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Sekhar
S
Duraisamy
Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Ronny
R
Drapkin
Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
R Scott
RS
Powers
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
Jason M
JM
Rohde
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
Matthew B
MB
Boxer
Department of Medicine, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Kwok-Kin
KK
Wong
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.
Geoffrey D
GD
Girnun
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D005947:Glucose / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D006019:Glycolysis; D019073:HT29 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D009368:Neoplasm Transplantation; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D046912:Multiprotein Complexes; D005973:Glutamine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C000597251:PCK2 protein, human; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose