Author/Authors :
Tong، نويسنده , , Wing-Hang and Sourbier، نويسنده , , Carole and Kovtunovych، نويسنده , , Gennady and Jeong، نويسنده , , Suh Young and Vira، نويسنده , , Manish and Ghosh، نويسنده , , Manik and Romero، نويسنده , , Vladimir Valera and Sougrat، نويسنده , , Rachid and Vaulont، نويسنده , , Sophie and Viollet، نويسنده , , Benoit and Kim، نويسنده , , Yeong-Sang and Lee، نويسنده , , Sunmin and Trepel، نويسنده , , Jane and Srinivasan، نويسنده , , Ramaprasad and Bratslavsky، نويسنده , , Gennady and Yang، نويسنده , , Youfeng and Linehan، نويسنده , , W. Marston and Rouault، نويسنده , , Tracey A.، نويسنده ,
Abstract :
Summary
vation of the TCA cycle enzyme, fumarate hydratase (FH), drives a metabolic shift to aerobic glycolysis in FH-deficient kidney tumors and cell lines from patients with hereditary leiomyomatosis renal cell cancer (HLRCC), resulting in decreased levels of AMP-activated kinase (AMPK) and p53 tumor suppressor, and activation of the anabolic factors, acetyl-CoA carboxylase and ribosomal protein S6. Reduced AMPK levels lead to diminished expression of the DMT1 iron transporter, and the resulting cytosolic iron deficiency activates the iron regulatory proteins, IRP1 and IRP2, and increases expression of the hypoxia inducible factor HIF-1α, but not HIF-2α. Silencing of HIF-1α or activation of AMPK diminishes invasive activities, indicating that alterations of HIF-1α and AMPK contribute to the oncogenic growth of FH-deficient cells.
