Research ArticleMetabolism

p53 is regulated by aerobic glycolysis in cancer cells by the CtBP family of NADH-dependent transcriptional regulators

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Science Signaling  05 May 2020:
Vol. 13, Issue 630, eaau9529
DOI: 10.1126/scisignal.aau9529

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Protective p53 response

To fuel their rapid proliferation, tumor cells increase their rates of glycolysis, which not only generates precursors for biosynthetic pathways but also results in an increase in the NADH:NAD+ ratio. Birts et al. found that, in highly glycolytic cancer cells in vitro, the increased NADH:NAD+ ratio resulted in an increase in the abundance of the NADH-bound forms of CtBP family transcriptional regulators, which prevented their interaction with the p53-binding protein HDM2, thus enabling the accumulation of p53. The resulting expression of p53 target genes was required to maintain metabolic homeostasis, highlighting a role for p53 in protecting cells from glycolytic stress.

Abstract

High rates of glycolysis in cancer cells are a well-established characteristic of many human tumors, providing rapidly proliferating cancer cells with metabolites that can be used as precursors for anabolic pathways. Maintenance of high glycolytic rates depends on the lactate dehydrogenase–catalyzed regeneration of NAD+ from GAPDH-generated NADH because an increased NADH:NAD+ ratio inhibits GAPDH. Here, using human breast cancer cell models, we identified a pathway in which changes in the extramitochondrial-free NADH:NAD+ ratio signaled through the CtBP family of NADH-sensitive transcriptional regulators to control the abundance and activity of p53. NADH-free forms of CtBPs cooperated with the p53-binding partner HDM2 to suppress p53 function, and loss of these forms in highly glycolytic cells resulted in p53 accumulation. We propose that this pathway represents a “glycolytic stress response” in which the initiation of a protective p53 response by an increased NADH:NAD+ ratio enables cells to avoid cellular damage caused by mismatches between metabolic supply and demand.

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