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

Emma E. Vincent, Alexey Sergushichev, Takla Griss, Marie Claude Gingras, Bozena Samborska, Thierry Ntimbane, Paula P. Coelho, Julianna Blagih, Thomas C. Raissi, Luc Choinière, Gaëlle Bridon, Ekaterina Loginicheva, Breanna R. Flynn, Elaine C. Thomas, Jeremy M. Tavaré, Daina Avizonis, Arnim Pause, Douglas J.E. Elder, Maxim N. Artyomov, Russell G. Jones

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)195-207
Number of pages13
JournalMolecular cell
Volume60
Issue number2
DOIs
StatePublished - Oct 15 2015

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    Vincent, E. E., Sergushichev, A., Griss, T., Gingras, M. C., Samborska, B., Ntimbane, T., Coelho, P. P., Blagih, J., Raissi, T. C., Choinière, L., Bridon, G., Loginicheva, E., Flynn, B. R., Thomas, E. C., Tavaré, J. M., Avizonis, D., Pause, A., Elder, D. J. E., Artyomov, M. N., & Jones, R. G. (2015). Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth. Molecular cell, 60(2), 195-207. https://doi.org/10.1016/j.molcel.2015.08.013