Cells lacking the fumarase tumor suppressor are protected from apoptosis through a hypoxia-inducible factor-independent, AMPK-dependent mechanism.
Loss-of-function mutations of the tumor suppressor gene encoding fumarase (FH) occur in individuals with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC). We found that loss of FH activity conferred protection from apoptosis in normal human renal cells and fibroblasts. In FH-defective cells, both hypoxia-inducible factor 1α (HIF-1α) and HIF-2α accumulated, but they were not required for apoptosis protection. Conversely, AMP-activated protein kinase (AMPK) was activated and required, as evidenced by the finding that FH inactivation failed to protect AMPK-null mouse embryo fibroblasts (MEFs) and AMPK-depleted human renal cells. Activated AMPK was detected in renal cysts, which occur in mice with kidney-targeted deletion of Fh1 and in kidney cancers of HLRCC patients. In Fh1-null MEFs, AMPK activation was sustained by fumarate accumulation and not by defective energy metabolism. Addition of fumarate and succinate to kidney cells led to extracellular signal-regulated kinase 1/2 (ERK1/2) and AMPK activation, probably through a receptor-mediated mechanism. These findings reveal a new mechanism of tumorigenesis due to FH loss and an unexpected pro-oncogenic role for AMPK that is important in considering AMPK reactivation as a therapeutic strategy against cancer.
Department of Oncological Sciences, University of Torino, School of Medicine, Turin, Italy.
Chiara
C
Bardella
Martina
M
Olivero
Annalisa
A
Lorenzato
Massimo
M
Geuna
Julie
J
Adam
Linda
L
O'Flaherty
Pierre
P
Rustin
Ian
I
Tomlinson
Patrick J
PJ
Pollard
Maria Flavia
MF
Di Renzo
D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis / Q000378:metabolism; D002460:Cell Line; D005649:Fumarate Hydratase / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005650:Fumarates / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics; D018231:Leiomyomatosis / Q000235:genetics; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000096:biosynthesis / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000096:biosynthesis / Q000378:metabolism; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000032:analysis; D015398:Signal Transduction; D012878:Skin Neoplasms; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014594:Uterine Neoplasms; D000099162:Endothelial PAS Domain-Containing Protein 1
D055372:AMP-Activated Protein Kinases; D051792:Basic Helix-Loop-Helix Proteins; D005649:Fumarate Hydratase; D005650:Fumarates; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1