Abstract
SummaryThe 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.
Highlights
Since first highlighted in the last century, altered metabolism has been a consistent observation in cancer cells (Warburg, 1956).Recently, the identification of mutated Krebs cycle enzymes in familial cancer syndromes has linked altered metabolism and cancer directly
We demonstrate that reexpression of cytosolic fumarate hydratase (FH) in FH1-deficient mice is critical for the suppression of renal cyst development and restoration of defects in the arginine biosynthesis pathway
We have proposed previously that, in FH1KO mouse embryonic fibroblasts (MEFs), 2OG can be converted to isocitrate by isocitrate dehydrogenase (IDH), but isocitrate cannot be further metabolized to citrate, probably as a result of impaired Aconitase 2 activity due to succination
Summary
Since first highlighted in the last century, altered metabolism has been a consistent observation in cancer cells (Warburg, 1956).Recently, the identification of mutated Krebs cycle enzymes in familial cancer syndromes has linked altered metabolism and cancer directly (reviewed in Bayley and Devilee, 2010; Frezza et al, 2011a). Mutations in one of these enzymes, fumarate hydratase (FH), predispose individuals to hereditary leiomyomatosis and renal cell cancer (HLRCC) (Tomlinson et al, 2002). Affected individuals develop renal cysts, a phenotype that is recapitulated in FH1 (murine FH)-deficient mice (Pollard et al, 2007). Re-expression of cytosolic FH ameliorates constitutive activation of both the hypoxia and antioxidant response pathways in FH1-null cells, despite a persistent defect in oxidative metabolism (Adam et al, 2011; O’Flaherty et al, 2010). To corroborate our findings in vivo, we generated two transgenic murine models where either FH or extramitochondrial FH (FHcyt) is stably expressed from the
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