TY - JOUR
T1 - A Role for Cytosolic Fumarate Hydratase in Urea Cycle Metabolism and Renal Neoplasia
AU - Adam, Julie
AU - Yang, Ming
AU - Bauerschmidt, Christina
AU - Kitagawa, Mitsuhiro
AU - O'Flaherty, Linda
AU - Maheswaran, Pratheesh
AU - Özkan, Gizem
AU - Sahgal, Natasha
AU - Baban, Dilair
AU - Kato, Keiko
AU - Saito, Kaori
AU - Iino, Keiko
AU - Igarashi, Kaori
AU - Stratford, Michael
AU - Pugh, Christopher
AU - Tennant, Daniel A.
AU - Ludwig, Christian
AU - Davies, Benjamin
AU - Ratcliffe, Peter J.
AU - El-Bahrawy, Mona
AU - Ashrafian, Houman
AU - Soga, Tomoyoshi
AU - Pollard, Patrick J.
N1 - Funding Information:
This work was funded by Cancer Research UK (A13349, A14607, and A12027 to P.J.P.), a Grant-in-Aid for scientific research on Innovative Areas, Japan (no. 22134007 to T.S.), and the Yamagata Prefectural Government and City of Tsuruoka. The Wellcome Trust provided support to P.J.P. (WT091112MA), B.D., D.B., N.S., and the core Microscopy facility at the Wellcome Trust Centre (090532/Z/09/Z). The European Research Council has provided financial support under the European Community’s Seventh Framework Programme (FP7/2007-2013)/ERC grant agreement no. 310837 (P.J.P.). T.S. is a founder of Human Metabolome Technologies.
PY - 2013/5/30
Y1 - 2013/5/30
N2 - The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between metabolic dysregulation and cancer. Mutations in the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, and cancers, though the respective pathogenic roles of mitochondrial and cytosolic FH isoforms remain undefined. On the basis of comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells and tissues exhibit defects in the urea cycle/arginine metabolism. Remarkably, transgenic re-expression of cytosolic FH ameliorated both renal cyst development and urea cycle defects associated with renal-specific FH1 deletion in mice. Furthermore, acute arginine depletion significantly reduced the viability of FH1-deficient cells in comparison to controls. Our findings highlight the importance of extramitochondrial metabolic pathways in FH-associated oncogenesis and the urea cycle/arginine metabolism as a potential therapeutic target.
AB - The identification of mutated metabolic enzymes in hereditary cancer syndromes has established a direct link between metabolic dysregulation and cancer. Mutations in the Krebs cycle enzyme, fumarate hydratase (FH), predispose affected individuals to leiomyomas, renal cysts, and cancers, though the respective pathogenic roles of mitochondrial and cytosolic FH isoforms remain undefined. On the basis of comprehensive metabolomic analyses, we demonstrate that FH1-deficient cells and tissues exhibit defects in the urea cycle/arginine metabolism. Remarkably, transgenic re-expression of cytosolic FH ameliorated both renal cyst development and urea cycle defects associated with renal-specific FH1 deletion in mice. Furthermore, acute arginine depletion significantly reduced the viability of FH1-deficient cells in comparison to controls. Our findings highlight the importance of extramitochondrial metabolic pathways in FH-associated oncogenesis and the urea cycle/arginine metabolism as a potential therapeutic target.
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U2 - 10.1016/j.celrep.2013.04.006
DO - 10.1016/j.celrep.2013.04.006
M3 - Article
C2 - 23643539
AN - SCOPUS:84878532121
SN - 2211-1247
VL - 3
SP - 1440
EP - 1448
JO - Cell Reports
JF - Cell Reports
IS - 5
ER -
