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The nuclear-encoded Krebs cycle enzymes, fumarate hydratase (FH) and succinate dehydrogenase (SDHB, -C and -D), act as tumour suppressors. Germline mutations in FH predispose individuals to leiomyomas and renal cell cancer (HLRCC), whereas mutations in SDH cause paragangliomas and phaeochromocytomas (HPGL). In this study, we have shown that FH-deficient cells and tumours accumulate fumarate and, to a lesser extent, succinate. SDH-deficient tumours principally accumulate succinate. In situ analyses showed that these tumours also have over-expression of hypoxia-inducible factor 1alpha (HIF1alpha), activation of HIF1alphatargets (such as vascular endothelial growth factor) and high microvessel density. We found no evidence of increased reactive oxygen species in our cells. Our data provide in vivo evidence to support the hypothesis that increased succinate and/or fumarate causes stabilization of HIF1alpha a plausible mechanism, inhibition of HIF prolyl hydroxylases, has previously been suggested by in vitro studies. The basic mechanism of tumorigenesis in HPGL and HLRCC is likely to be pseudo-hypoxic drive, just as it is in von Hippel-Lindau syndrome.

Original publication

DOI

10.1093/hmg/ddi227

Type

Journal article

Journal

Hum Mol Genet

Publication Date

01/08/2005

Volume

14

Pages

2231 - 2239

Keywords

Carcinoma, Renal Cell, Citric Acid Cycle, Female, Fumarate Hydratase, Germ-Line Mutation, Humans, Leiomyoma, Neoplasms, Paraganglioma, Succinate Dehydrogenase, Tumor Cells, Cultured, Vascular Endothelial Growth Factor A