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

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...

Full description

Saved in:
Bibliographic Details
Published in:Science signaling 2020-05, Vol.13 (630)
Main Authors: Birts, Charles N, Banerjee, Arindam, Darley, Matthew, Dunlop, Charles R, Nelson, Sarah, Nijjar, Sharandip K, Parker, Rachel, West, Jonathan, Tavassoli, Ali, Rose-Zerilli, Matthew J J, Blaydes, Jeremy P
Format: Article
Language:English
Subjects:
Accumulation
Aerobiosis
Breast cancer
Cancer
Cell culture
Cell Line, Tumor
Cell proliferation
Gene expression
Gene Expression Regulation, Neoplastic
Glyceraldehyde-3-phosphate dehydrogenase
Glycolysis
Homeostasis
Humans
L-Lactate dehydrogenase
Lactate dehydrogenase
Lactic acid
Metabolism
Metabolites
NAD
NAD - genetics
NAD - metabolism
NADH
Neoplasms - genetics
Neoplasms - metabolism
Nicotinamide adenine dinucleotide
p53 Protein
Precursors
Regeneration
Regulators
Transcription
Transcription Factors - genetics
Transcription Factors - metabolism
Tumor cells
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1945-0877
1937-9145
DOI:10.1126/scisignal.aau9529