Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth

Mol Cell. 2015 Oct 15;60(2):195-207. doi: 10.1016/j.molcel.2015.08.013.


Cancer cells adapt metabolically to proliferate under nutrient limitation. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell proliferation. We found that glucose deprivation stimulated re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote glucose-independent cell proliferation. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine via the activity of mitochondrial PEP-carboxykinase (PCK2). Under these conditions, glutamine-derived PEP was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. PCK2 expression was required to maintain tumor cell proliferation under limited-glucose conditions in vitro and tumor growth in vivo. Elevated PCK2 expression is observed in several human tumor types and enriched in tumor tissue from non-small-cell lung cancer (NSCLC) patients. Our results define a role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological / genetics
  • Animals
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Citric Acid Cycle / genetics
  • Gene Expression Regulation, Neoplastic*
  • Gluconeogenesis / genetics*
  • Glucose / deficiency
  • Glutamine / metabolism
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Metabolomics
  • Mice
  • Mice, Nude
  • Mitochondria / metabolism
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Phosphoenolpyruvate / metabolism
  • Phosphoenolpyruvate Carboxykinase (ATP) / genetics
  • Phosphoenolpyruvate Carboxykinase (ATP) / metabolism*
  • Purines / biosynthesis
  • Pyruvic Acid / metabolism
  • Serine / biosynthesis


  • Purines
  • Glutamine
  • Serine
  • Phosphoenolpyruvate
  • Pyruvic Acid
  • PCK2 protein, human
  • Phosphoenolpyruvate Carboxykinase (ATP)
  • Glucose

Associated data

  • GEO/GSE66556