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Pyruvate carboxylase is required for glutamine-independent growth of tumor cells
Open accessAbstract
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.
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“Additionally, metabolic profiling has revealed that suppression of GLS1 induces a compensatory anaplerotic mechanism via pyruvate carboxylase (PC), which allows the release of a glutamine-independent supply of TCA intermediates by catalyzing the transformation of pyruvate to oxaloacetate153.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [153]
In the citing paper
“Likewise, cells that are addicted to glutamine become dependent on PC for growth when glutamine metabolism is suppressed; conversely, cells with high basal PC activity are generally more resistant to interruption of glutamine metabolism (87).”
From Regulation and function of the mammalian tricarboxylic acid cycle (2023) · cites this paper as [87]
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Metadata
- Authors
- Cheng, T., Sudderth, J., Yang, C., Mullen, A. R., Jin, E. S., Matés, J. M., & DeBerardinis, R. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Advanced Imaging Research Center,
- Universidad de Málaga (ES)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-05-09
- Volume
- 108
- Issue
- 21
- Pages
- 8674-8679
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3102381
- OpenAlex
- W2044565982
- Cited by
- 475
- References
- 31
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 24 · 2023: 25 · 2022: 35 · 2021: 42 · 2020: 30 · 2019: 48 · 2018: 26 · 2017: 38 · 2016: 41 · 2015: 38 · 2014: 31 · 2013: 24 · 2012: 20
- FWCI
- 9.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (T32GM083831)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK072565, K08DK072565, K01DK078933, DK078933)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- pyruvate carboxylase, glutamine addiction, glutaminase, anaplerosis, cancer metabolism, glioblastoma, glutaminolysis, glutamine metabolism, tumor metabolic reprogramming
- MeSH terms
- Citric Acid Cycle, Glioblastoma, Glutaminase, Glutamine, Humans, Pyruvate Carboxylase, Pyruvic Acid, Cell Line, Tumor, Cell Proliferation
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