The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect.

Journal Article (Journal Article)

Aerobic glycolysis in cancer cells, also known as the 'Warburg effect', is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein also regulates its activity. Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.

Full Text

Duke Authors

Cited Authors

  • Woodford, MR; Baker-Williams, AJ; Sager, RA; Backe, SJ; Blanden, AR; Hashmi, F; Kancherla, P; Gori, A; Loiselle, DR; Castelli, M; Serapian, SA; Colombo, G; Haystead, TA; Jensen, SM; Stetler-Stevenson, WG; Loh, SN; Schmidt, LS; Linehan, WM; Bah, A; Bourboulia, D; Bratslavsky, G; Mollapour, M

Published Date

  • August 2021

Published In

Volume / Issue

  • 28 / 8

Start / End Page

  • 662 - 670

PubMed ID

  • 34381247

Pubmed Central ID

  • PMC9278990

Electronic International Standard Serial Number (EISSN)

  • 1545-9985

Digital Object Identifier (DOI)

  • 10.1038/s41594-021-00633-2

Language

  • eng

Conference Location

  • United States