Pyruvate carboxylase is required for glutamine-independent growth of tumor cells

Tzuling Cheng, Jessica Sudderth, Chendong Yang, Andrew R. Mullen, Eunsook S. Jin, José M. Matés, Ralph J. DeBerardinis

Research output: Contribution to journalArticle

235 Citations (Scopus)

Abstract

Tumor cells require a constant supply of macromolecular precursors, and interrupting this supply has been proposed as a therapeutic strategy in cancer. Precursors for lipids, nucleic acids, and proteins are generated in the tricarboxylic acid (TCA) cycle and removed from the mitochondria to participate in biosynthetic reactions. Refilling the pool of precursor molecules (anaplerosis) is therefore crucial to maintain cell growth. Many tumor cells use glutamine to feed anaplerosis. Here we studied how "glutamine- addicted" cells react to interruptions of glutamine metabolism. Silencing of glutaminase (GLS), which catalyzes the first step in glutamine-dependent anaplerosis, suppressed but did not eliminate the growth of glioblastoma cells in culture and in vivo. Profiling metabolic fluxes in GLS-suppressed cells revealed induction of a compensatory anaplerotic mechanism catalyzed by pyruvate carboxylase (PC), allowing the cells to use glucose-derived pyruvate rather than glutamine for anaplerosis. Although PC was dispensable when glutamine was available, forcing cells to adapt to low-glutamine conditions rendered them absolutely dependent on PC for growth. Furthermore, in other cell lines, measuring PC activity in nutrient-replete conditions predicted dependence on specific anaplerotic enzymes. Cells with high PC activity were resistant to GLS silencing and did not require glutamine for survival or growth, but displayed suppressed growth when PC was silenced. Thus, PC-mediated, glucose-dependent anaplerosis allows cells to achieve glutamine independence. Induction of PC during chronic suppression of glutamine metabolism may prove to be a mechanism of resistance to therapies targeting glutaminolysis.

Original languageEnglish (US)
Pages (from-to)8674-8679
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number21
DOIs
StatePublished - May 24 2011

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Pyruvate Carboxylase
Glutamine
Growth
Neoplasms
Glutaminase
Nucleic Acid Precursors
Glucose
Citric Acid Cycle
Glioblastoma
Pyruvic Acid
Mitochondria
Cell Culture Techniques

Keywords

  • Cancer metabolism
  • Metabolic flux analysis
  • Metabolomics
  • Warburg effect

ASJC Scopus subject areas

  • General

Cite this

Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. / Cheng, Tzuling; Sudderth, Jessica; Yang, Chendong; Mullen, Andrew R.; Jin, Eunsook S.; Matés, José M.; DeBerardinis, Ralph J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 21, 24.05.2011, p. 8674-8679.

Research output: Contribution to journalArticle

Cheng, Tzuling ; Sudderth, Jessica ; Yang, Chendong ; Mullen, Andrew R. ; Jin, Eunsook S. ; Matés, José M. ; DeBerardinis, Ralph J. / Pyruvate carboxylase is required for glutamine-independent growth of tumor cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 21. pp. 8674-8679.
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