Glutamine is an amino acid that human cells can synthesize, so it is classed as nonessential. Even so, some cancer cells grown in the laboratory stop growing or die when glutamine is withheld. Researchers call this dependence glutamine addiction.
What the research shows
- Most cancers rely on a high rate of aerobic glycolysis, yet some cancer cell lines also depend on glutamine even though it can be made from glucose [1].
- The demand for glutamine is not explained only by its role as a nitrogen donor for nucleotides and amino acids. Glutamine also supports the uptake of essential amino acids and keeps TOR kinase active [1].
- In many cancer cells glutamine is the main mitochondrial fuel. It is needed to maintain mitochondrial membrane potential and to produce the NADPH used for redox control and macromolecule synthesis [1].
- Glutamine contributes to energy production, protects cells against oxidative stress, and complements glucose in building macromolecules [2].
- The oncogene Myc can trigger this dependence by switching on genes needed for glutamine breakdown (glutaminolysis) [3].
Wise et al. reported that Myc-driven glutaminolysis exceeded the amount of glutamine needed for protein and nucleotide synthesis. It reprogrammed mitochondrial metabolism so that cell viability and TCA-cycle anaplerosis depended on glutamine catabolism, and less glucose-derived carbon entered the TCA cycle. In their system this did not require concurrent PI3K or AKT activation [3].
What this does not show
These findings come from cell lines and experimental models. They describe a metabolic dependence, not a treatment. Strategies that target glutamine metabolism in tumors are still being developed and studied [2].
References
- D. R. Wise and C. B. Thompson, “Glutamine addiction: a new therapeutic target in cancer,” Trends Biochem. Sci., vol. 35, no. 8, pp. 427–433, Aug. 2010. doi: 10.1016/j.tibs.2010.05.003. PMID: 20570523.
- R. J. DeBerardinis and T. Cheng, “Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer,” Oncogene, vol. 29, no. 3, pp. 313–324 (epub Nov. 2, 2009). doi: 10.1038/onc.2009.358. PMID: 19881548.
- D. R. Wise et al., “Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction,” Proc. Natl. Acad. Sci. U.S.A., vol. 105, no. 48, pp. 18782–18787, Nov. 2008. doi: 10.1073/pnas.0810199105. PMID: 19033189.
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Department of Molecular Diagnostics, Faculty of Biomedical Sciences, University of Benghazi, Libya
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