As oxygen is essential for many metabolic pathways, tumour hypoxia may impair cancer cell proliferation1,2,3,4. However, the limiting metabolites for proliferation under hypoxia and in tumours are unknown. Here, we assessed proliferation of a collection of cancer cells following inhibition of the mitochondrial electron transport chain (ETC), a major metabolic pathway requiring molecular oxygen5. Sensitivity to ETC inhibition varied across cell lines, and subsequent metabolomic analysis uncovered aspartate availability as a major determinant of sensitivity. Cell lines least sensitive to ETC inhibition maintain aspartate levels by importing it through an aspartate/glutamate transporter, SLC1A3. Genetic or pharmacologic modulation of SLC1A3 activity markedly altered cancer cell sensitivity to ETC inhibitors. Interestingly, aspartate levels also decrease under low oxygen, and increasing aspartate import by SLC1A3 provides a competitive advantage to cancer cells at low oxygen levels and in tumour xenografts. Finally, aspartate levels in primary human tumours negatively correlate with the expression of hypoxia markers, suggesting that tumour hypoxia is sufficient to inhibit ETC and, consequently, aspartate synthesis in vivo. Therefore, aspartate may be a limiting metabolite for tumour growth, and aspartate availability could be targeted for cancer therapy.
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We thank all members of the Birsoy lab for helpful suggestions, and C. Moraes, and I. F. M. de Coo for providing the WT 143B and CYTB 143B cell lines. The KP cell lines are gifts from N. Bardeesy and T. Papagiannakopoulos. We also thank A. M. Hosios for natural abundance correction. This research is supported by an EMBO long-term fellowship to J.G.-B. (EMBO ALTF 887-2016). Profiling of human glioblastoma samples was supported by the Friedberg Charitable Foundation and Sohn Foundation grants to M.S. and Rachel Molly Markoff Foundation grant to M.S. and R.L.P. R.L.P. was supported by the NIH (R21CA198543), K.B. was supported by K22 (1K22CA193660), DP2 (DP2 OD024174-01), Irma-Hirschl Trust, AACR NextGen Grant and the Breast Cancer Research Foundation, and is a Searle Scholar, Sidney Kimmel Scholar and Basil O’Connor Scholar of March of Dimes.
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Nature Reviews Cancer (2018)