| Autor: |
Julie Adam, Ming Yang, Christina Bauerschmidt, Mitsuhiro Kitagawa, Linda O’Flaherty, Pratheesh Maheswaran, Gizem Özkan, Natasha Sahgal, Dilair Baban, Keiko Kato, Kaori Saito, Keiko Iino, Kaori Igarashi, Michael Stratford, Christopher Pugh, Daniel A. Tennant, Christian Ludwig, Benjamin Davies, Peter J. Ratcliffe, Mona El-Bahrawy, Houman Ashrafian, Tomoyoshi Soga, Patrick J. Pollard |
| Jazyk: |
angličtina |
| Rok vydání: |
2013 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 3, Iss 5, Pp 1440-1448 (2013) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2013.04.006 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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