1. Glutamine addiction promotes glucose oxidation in triple-negative breast cancer
- Author
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Quek, L-E, van Geldermalsen, M, Guan, YF, Wahi, K, Mayoh, C, Balaban, S, Pang, A, Wang, Q, Cowley, MJ, Brown, KK, Turner, N, Hoy, AJ, Holst, J, Quek, L-E, van Geldermalsen, M, Guan, YF, Wahi, K, Mayoh, C, Balaban, S, Pang, A, Wang, Q, Cowley, MJ, Brown, KK, Turner, N, Hoy, AJ, and Holst, J
- Abstract
Glutamine is a conditionally essential nutrient for many cancer cells, but it remains unclear how consuming glutamine in excess of growth requirements confers greater fitness to glutamine-addicted cancers. By contrasting two breast cancer subtypes with distinct glutamine dependencies, we show that glutamine-indispensable triple-negative breast cancer (TNBC) cells rely on a non-canonical glutamine-to-glutamate overflow, with glutamine carbon routed once through the TCA cycle. Importantly, this single-pass glutaminolysis increases TCA cycle fluxes and replenishes TCA cycle intermediates in TNBC cells, a process that achieves net oxidation of glucose but not glutamine. The coupling of glucose and glutamine catabolism appears hard-wired via a distinct TNBC gene expression profile biased to strip and then sequester glutamine nitrogen, but hampers the ability of TNBC cells to oxidise glucose when glutamine is limiting. Our results provide a new understanding of how metabolically rigid TNBC cells are sensitive to glutamine deprivation and a way to select vulnerable TNBC subtypes that may be responsive to metabolic-targeted therapies.
- Published
- 2022