Glutamine addiction promotes glucose oxidation in triple-negative breast cancer

Quek, LE; 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

Author(s): Quek, LE; 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;
Details: Publication Year 2022-08,Volume 41,Issue #34,Page 4066-4078
Journal Title: Oncogene
Publication Type: Research article
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.
Keywords: Cell Line, Tumor; Citric Acid Cycle; Glucose/metabolism; Glutamic Acid/metabolism; *Glutamine/metabolism; Humans; *Triple Negative Breast Neoplasms/genetics/metabolism
Department(s): Laboratory Research
PubMed ID: 35851845
Publisher's Version: https://doi.org/10.1038/s41388-022-02408-5
Open Access at Publisher's Site: https://doi.org/10.1038/s41388-022-02408-5
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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