Editors' ChoiceCancer

Cancer's Food Network

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Science Translational Medicine  31 Aug 2011:
Vol. 3, Issue 98, pp. 98ec139
DOI: 10.1126/scitranslmed.3003106

Some dining companions offer no drama—whether it's curries, cobblers, or zuppa di pesce, their food choices are predictable. Like these palates, cancer cells can display nutrient preferences and become addicted to, for example, glucose or glutamine. This variation in fuel dependency may have a root in oncogenic events, cellular origin, or differentiation status and may provide insights into possible therapeutic approaches. To determine the phenotypic response to glutamine deprivation (glutamine index) and the corresponding genotypic alterations, Kung and colleagues performed a comprehensive analysis of glutamine dependence among breast cancer subtypes.

Mitochondrial glutaminases (GLS) convert the amino acid glutamine to glutamate, which is then converted to α-ketoglutarate. This multifunctional molecule can serve as a substrate for (i) the energy-producing Krebs cycle, (ii) amino acid catabolism, (iii) synthesis of the antioxidant glutathione, or (iv) production of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) for use in the synthesis of macromolecules. But in some cell types, glutamine synthetase (GS), which is encoded by the glutamate-ammonia ligase (GLUL) gene, catalyzes the reverse reaction by combining glutamate and ammonia and generating glutamine. Through a series of robust experiments, Kung et al. demonstrated a cell lineage–specific difference in the response of human basal versus luminal breast cancer cells to glutamine deprivation. Compared with four luminal-type breast cancer cell lines, three basal-type cell lines showed significantly reduced growth rates, more prominent cell death, and a decrease in adenosine triphosphate production in response to glutamine deprivation. The basal cells also displayed higher levels of glutamine consumption and lower intracellular glutamine concentrations than did the luminal cells. The researchers showed that this distinct pattern of glutamine dependence was associated with differential expression of GLS and GS mRNA and protein in breast cancer cell lines, primary human breast cancer tissue, and normal breast epithelia. Subtype-specific expression of the enzyme-encoding genes was regulated by GATA3, a key luminal transcription factor.

These data suggest that glutamine metabolism is a valid target for the treatment of solid tumors and hematological malignancies that are addicted to glutamine for survival, proliferation, invasion, and energy production. One caveat of this strategy could be the microenvironment symbiosis and ability of adjacent nontransformed cells such as fibroblasts and macrophages to provide glutamine to the addicted cells. GS inhibition combined with glutamine-targeted therapy may circumvent this problem. After all, a system, no matter how complex, cannot function without fuel; thus, it may be time to define the favorite foods of individual cancer cell types.

H.-N. Kung et al., Glutamine synthetase is a genetic determinant of cell type–specific glutamine independence in breast epithelia. PLoS Genet. 7, e1002229 (2011). [Full text]

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