Journal
NATURE CELL BIOLOGY
Volume 20, Issue 7, Pages 775-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41556-018-0118-z
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Funding
- EMBO long-term fellowship [EMBO ALTF 887-2016]
- Friedberg Charitable Foundation
- Sohn Foundation grants
- Rachel Molly Markoff Foundation grant
- NIH [R21CA198543]
- Irma-Hirschl Trust
- AACR NextGen Grant
- Breast Cancer Research Foundation
- [1K22CA193660]
- [DP2 OD024174-01]
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As oxygen is essential for many metabolic pathways, tumour hypoxia may impair cancer cell proliferation1-4. 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 oxygen(5). 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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