TY - JOUR
T1 - The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect
AU - Woodford, Mark R.
AU - Baker-Williams, Alexander J.
AU - Sager, Rebecca A.
AU - Backe, Sarah J.
AU - Blanden, Adam R.
AU - Hashmi, Fiza
AU - Kancherla, Priyanka
AU - Gori, Alessandro
AU - Loiselle, David R.
AU - Castelli, Matteo
AU - Serapian, Stefano A.
AU - Colombo, Giorgio
AU - Haystead, Timothy A.
AU - Jensen, Sandra M.
AU - Stetler-Stevenson, William G.
AU - Loh, Stewart N.
AU - Schmidt, Laura S.
AU - Linehan, W. Marston
AU - Bah, Alaji
AU - Bourboulia, Dimitra
AU - Bratslavsky, Gennady
AU - Mollapour, Mehdi
N1 - Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85112330274
U2 - 10.1038/s41594-021-00633-2
DO - 10.1038/s41594-021-00633-2
M3 - Article
C2 - 34381247
SN - 1545-9993
VL - 28
SP - 662
EP - 670
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 8
ER -