2. Academic Validation
  3. The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect

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

  • Nat Struct Mol Biol. 2021 Aug;28(8):662-670. doi: 10.1038/s41594-021-00633-2.
Mark R Woodford 1 2 3,  Alexander J Baker-Williams 1 2 3,  Rebecca A Sager 1 2 3,  Sarah J Backe 1 2 3,  Adam R Blanden 2 3,  Fiza Hashmi 1 2 3,  Priyanka Kancherla 1,  Alessandro Gori 4,  David R Loiselle 5,  Matteo Castelli 6,  Stefano A Serapian 6,  Giorgio Colombo 6,  Timothy A Haystead 5,  Sandra M Jensen 7,  William G Stetler-Stevenson 7,  Stewart N Loh 2 3,  Laura S Schmidt 8 9,  W Marston Linehan 9,  Alaji Bah 2 3,  Dimitra Bourboulia 1 2 3,  Gennady Bratslavsky 10 11 12,  Mehdi Mollapour 13 14 15
Affiliations

Affiliations

  • 1 Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA.
  • 2 Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA.
  • 3 Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA.
  • 4 Istituto di Scienze e Tecnologie Chimiche 'Giulio Natta' - SCITEC, Milan, Italy.
  • 5 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
  • 6 Department of Chemistry, University of Pavia, Pavia, Italy.
  • 7 Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, The National Institutes of Health, Bethesda, MD, USA.
  • 8 Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • 9 Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • 10 Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 11 Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 12 Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 13 Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 14 Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
  • 15 Upstate Cancer Center, SUNY Upstate Medical University, Syracuse, NY, USA. [email protected].
PMID: 34381247 DOI: 10.1038/s41594-021-00633-2
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.

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