Accumulation of Krebs cycle intermediates and over-expression of HIF1 alpha in tumours which result from germline FH and SDH mutations

Pollard, P. J., Briere, J. J., Alam, N. A., Barwell, J., Barclay, E., Wortham, N. C., Hunt, T., Mitchell, M., Olpin, S., Moat, Stuart James, Hargreaves, I. P., Heales, S. J., Chung, Y. L., Griffiths, J. R., Dalgleish, A., McGrath, J. A., Gleeson, M. J., Hodgson, S. V., Poulsom, R., Rustin, P. and Tomlinson, I. P. M. 2005. Accumulation of Krebs cycle intermediates and over-expression of HIF1 alpha in tumours which result from germline FH and SDH mutations. Human Molecular Genetics 14 (15) , pp. 2231-2239. 10.1093/hmg/ddi227

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Abstract

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 1? (HIF1?), activation of HIF1? targets (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 HIF1? 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General)
Publisher:	Oxford University Press
ISSN:	1460-2083
Last Modified:	04 Jun 2017 01:30
URI:	https://orca.cardiff.ac.uk/id/eprint/86

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