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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • Glucose / metabolism*
  • Glutamine / metabolism*
  • Glycolysis
  • HT29 Cells
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Multiprotein Complexes / metabolism*
  • Neoplasm Transplantation
  • Phosphoenolpyruvate Carboxykinase (ATP) / metabolism*
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Multiprotein Complexes
  • Glutamine
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • PCK2 protein, human
  • Phosphoenolpyruvate Carboxykinase (ATP)
  • Glucose