TY - JOUR AU - Yan, Ming AU - Gingras, Marie-Claude AU - Dunlop, Elaine A. AU - Nouët, Yann AU - Dupuy, Fanny AU - Jalali, Zahra AU - Possik, Elite AU - Coull, Barry J. AU - Kharitidi, Dmitri AU - Dydensborg, Anders Bondo AU - Faubert, Brandon AU - Kamps, Miriam AU - Sabourin, Sylvie AU - Preston, Rachael S. AU - Davies, David Mark AU - Roughead, Taren AU - Chotard, Laëtitia AU - van Steensel, Maurice A.M. AU - Jones, Russell AU - Tee, Andrew R. AU - Pause, Arnim T1 - The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation PY - 2014/06/02/ AB - The Warburg effect is a tumorigenic metabolic adaptation process characterized by augmented aerobic glycolysis, which enhances cellular bioenergetics. In normal cells, energy homeostasis is controlled by AMPK; however, its role in cancer is not understood, as both AMPK-dependent tumor-promoting and -inhibiting functions were reported. Upon stress, energy levels are maintained by increased mitochondrial biogenesis and glycolysis, controlled by transcriptional coactivator PGC-1α and HIF, respectively. In normoxia, AMPK induces PGC-1α, but how HIF is activated is unclear. Germline mutations in the gene encoding the tumor suppressor folliculin (FLCN) lead to Birt-Hogg-Dubé (BHD) syndrome, which is associated with an increased cancer risk. FLCN was identified as an AMPK binding partner, and we evaluated its role with respect to AMPK-dependent energy functions. We revealed that loss of FLCN constitutively activates AMPK, resulting in PGC-1α–mediated mitochondrial biogenesis and increased ROS production. ROS induced HIF transcriptional activity and drove Warburg metabolic reprogramming, coupling AMPK-dependent mitochondrial biogenesis to HIF-dependent metabolic changes. This reprogramming stimulated cellular bioenergetics and conferred a HIF-dependent tumorigenic advantage in FLCN-negative cancer cells. Moreover, this pathway is conserved in a BHD-derived tumor. These results indicate that FLCN inhibits tumorigenesis by preventing AMPK-dependent HIF activation and the subsequent Warburg metabolic transformation. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI71749 VL - 124 IS - 6 UR - https://doi.org/10.1172/JCI71749 SP - 2640 EP - 2650 PB - The American Society for Clinical Investigation ER -