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

Abstract

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.

• Authors: Mark R Woodford, Alexander J Baker-Williams, Rebecca A Sager, Sarah J Backe, Adam R Blanden, Fiza Hashmi, Priyanka Kancherla, Alessandro Gori, David R Loiselle, Matteo Castelli, Stefano A Serapian, Giorgio Colombo, Timothy A Haystead, Sandra M Jensen, William G Stetler-Stevenson, Stewart N Loh, Laura S Schmidt, W Marston Linehan, Alaji Bah, Dimitra Bourboulia, Gennady Bratslavsky, Mehdi Mollapour
• Journal: Nature structural & molecular biology (Nat Struct Mol Biol) Vol. 28 Issue 8 Pg. 662-670 (08 2021) ISSN: 1545-9985 [Electronic] United States
• PMID: 34381247 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Chemical References

• FLCN protein, human
• Proto-Oncogene Proteins
• Tumor Suppressor Proteins
• Lactate Dehydrogenase 5

Topics

• Catalytic Domain (physiology)
• Cell Line, Tumor
• Cell Proliferation
• Gene Expression Regulation, Neoplastic (genetics)
• Glycolysis (physiology)
• HEK293 Cells
• Humans
• Lactate Dehydrogenase 5 (antagonists & inhibitors, metabolism)
• Neoplasms (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Signal Transduction
• Tumor Suppressor Proteins (metabolism)