Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours

Javier Garcia-Bermudez, Lou Baudrier, Konnor La, Xiphias Ge Zhu, Justine Fidelin, Vladislav O. Sviderskiy, Thales Papagiannakopoulos, Henrik Molina, Matija Snuderl, Caroline A. Lewis, Richard L. Possemato, Klvanç Birsoy

Research output: Contribution to journalArticlepeer-review

152 Scopus citations

Abstract

As oxygen is essential for many metabolic pathways, tumour hypoxia may impair cancer cell proliferation 1-4 . 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.

Original languageEnglish (US)
Pages (from-to)775-781
Number of pages7
JournalNature cell biology
Volume20
Issue number7
DOIs
StatePublished - Jul 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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