| First Author | Yan M | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 6 | Pages | 2640-50 |
| PubMed ID | 24762438 | Mgi Jnum | J:212826 |
| Mgi Id | MGI:5582327 | Doi | 10.1172/JCI71749 |
| Citation | Yan M, et al. (2014) The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. J Clin Invest 124(6):2640-50 |
| abstractText | 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-1alpha and HIF, respectively. In normoxia, AMPK induces PGC-1alpha, but how HIF is activated is unclear. Germline mutations in the gene encoding the tumor suppressor folliculin (FLCN) lead to Birt-Hogg-Dube (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-1alpha-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. |
