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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.

Original publication

DOI

10.1128/MCB.06160-11

Type

Journal article

Journal

Mol Cell Biol

Publication Date

08/2012

Volume

32

Pages

3081 - 3094

Keywords

AMP-Activated Protein Kinases, Animals, Apoptosis, Basic Helix-Loop-Helix Transcription Factors, Cell Line, Fumarate Hydratase, Fumarates, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Kidney Neoplasms, Leiomyomatosis, Mice, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Neoplastic Syndromes, Hereditary, RNA Interference, RNA, Small Interfering, Reactive Oxygen Species, Signal Transduction, Skin Neoplasms, Tumor Suppressor Proteins, Uterine Neoplasms