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Metabolism

Acetate nourishes stressed tumour cells

Nature Reviews Cancer volume 15, page 67 (2015)Cite this article

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Schug and Peck et al. assessed the role of lipogenesis in hypoxia and nutrient-poor conditions (metabolic stress). They traced 13C-labelled glucose in several cancer cell lines cultured using a customized serum that approximates physiological nutrient conditions. In normoxic conditions, glucose was mostly used in the tricarboxylic acid (TCA) cycle, as well as for fatty acid synthesis. In hypoxia, the 13C labelling of fatty acids and TCA intermediates was considerably decreased, and further analyses of spheroids and xenograft tumours (which both have oxygen gradients that can induce metabolic stress) revealed high levels of acetyl-CoA and fatty acid precursors when fatty acid synthase or ACSS2 were inhibited. This suggests that hypoxia induces a dependence on acetate, rather than glucose, as a carbon source for fatty acid synthesis. Next, the authors traced 13C-acetate and found that the pool of acetyl-CoA labelled with 13C increased in hypoxic and nutrient-poor conditions. This and further experiments showed that acetate is the main source of acetyl-CoA in conditions of metabolic stress.

These authors found that ACSS2 knockdown was the top hit in a screen for inducing growth inhibition of several breast and prostate cancer cell lines cultured in hypoxia. They also found that ACSS2 expression correlates with breast and prostate cancer progression. Furthermore, ACSS2 levels correlated with acetate uptake, and hypoxia and lipid depletion induced the expression of ACSS2. ACSS2 knockdown in several cancer cell lines that were grown as xenografts decreased tumour growth, demonstrating that acetate is an important nutrient for tumour cells undergoing metabolic stress.

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References

  1. Schug, Z. T. & Peck, B. et al. Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27, 57–71 (2015)

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  1. Gemma K. Alderton
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Alderton, G. Acetate nourishes stressed tumour cells. Nat Rev Cancer 15, 67 (2015). https://doi.org/10.1038/nrc3899

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