Document Detail


Pyruvate carboxylase is required for glutamine-independent growth of tumor cells.
MedLine Citation:
PMID:  21555572     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Tzuling Cheng; Jessica Sudderth; Chendong Yang; Andrew R Mullen; Eunsook S Jin; José M Matés; Ralph J DeBerardinis
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-05-09
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  108     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-25     Completed Date:  2011-10-07     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  8674-9     Citation Subset:  IM    
Affiliation:
Department of Pediatrics, Advanced Imaging Research Center, and McDermott Center for Human Growth and Development, University of Texas-Southwestern Medical Center, Dallas, TX 75390-9063, USA.
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MeSH Terms
Descriptor/Qualifier:
Cell Line, Tumor
Cell Proliferation*
Citric Acid Cycle
Glioblastoma / metabolism*,  pathology
Glutaminase / antagonists & inhibitors
Glutamine / deficiency,  metabolism*
Humans
Pyruvate Carboxylase / metabolism,  physiology*
Pyruvic Acid / metabolism
Grant Support
ID/Acronym/Agency:
5T32GM083831-02/GM/NIGMS NIH HHS; DK072565/DK/NIDDK NIH HHS; DK078933/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
127-17-3/Pyruvic Acid; 56-85-9/Glutamine; EC 3.5.1.2/Glutaminase; EC 6.4.1.1/Pyruvate Carboxylase
Comments/Corrections

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