Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations.
By Patrick J. Pollard, J. Briere, N. A. Alam, J. Barwell, E. Barclay, Noel C. Wortham, T. Hunt, M. Mitchell, S. Olpin, S. Moat and 11 more. Human Molecular Genetics, 2005
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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.
Subfields: Cancer Research, Endocrinology, Diabetes and Metabolism, Surgery
View Paper: https://www.semanticscholar.org/paper/130e78256e807326b1dc7b70096cbbfc33ce5355
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Citations in the corpus
- Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases (2011, background): “Mutations targeting FH and SDH lead to similar increase in the PHD substrate, HIF-1a (Isaacs et al., 2005; Pollard et al., 2005; Selak et al., 2005).”
- Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer (2006, background): “It is possible that due to its structure, fumarate interacts better with PHDs. Subsequent support for the biochemical role of succinate and fumarate in SDH- and FH-deficient tumours came from metabolomic studies of these tumours (Pollard et al., 2005b).”
- Targeting Metabolism for Cancer Therapy (2017, background): “A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript (Hewitson et al., 2007; Pollard et al., 2005; Selak et al., 2005).”
- Cancer cell metabolism: Warburg and beyond. (2008, background): “…has been proposed that loss of succinate dehydrogenase and fumarate hydratase causes an accumulation of succinate or fumarate, respectively, leading to inhibition of the prolyl hydroxylases that mark HIF for VHL-mediated degradation (Isaacs et al., 2005; Pollard et al., 2005; Selak et al., 2005).”
- Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. (2012, background): “Thus far, all functionally characterized FH or SDH mutations result in either a complete loss or reduction of enzymatic activity (Tomlinson et al. 2002; Pollard et al. 2005), indicating that both FH and SDH function as tumor suppressors.”