Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations
- PMID: 15987702
- DOI: 10.1093/hmg/ddi227
Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations
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 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.
Similar articles
-
Increased HIF1 alpha in SDH and FH deficient tumors does not cause microsatellite instability.Int J Cancer. 2007 Sep 15;121(6):1386-9. doi: 10.1002/ijc.22819. Int J Cancer. 2007. PMID: 17520677
-
Evidence of increased microvessel density and activation of the hypoxia pathway in tumours from the hereditary leiomyomatosis and renal cell cancer syndrome.J Pathol. 2005 Jan;205(1):41-9. doi: 10.1002/path.1686. J Pathol. 2005. PMID: 15586379
-
Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer.Oncogene. 2006 Aug 7;25(34):4675-82. doi: 10.1038/sj.onc.1209594. Oncogene. 2006. PMID: 16892081 Review.
-
Germline fumarate hydratase mutations in patients with ovarian mucinous cystadenoma.Eur J Hum Genet. 2006 Jul;14(7):880-3. doi: 10.1038/sj.ejhg.5201630. Epub 2006 Apr 26. Eur J Hum Genet. 2006. PMID: 16639410
-
The TCA cycle and tumorigenesis: the examples of fumarate hydratase and succinate dehydrogenase.Ann Med. 2003;35(8):632-9. doi: 10.1080/07853890310018458. Ann Med. 2003. PMID: 14708972 Review.
Cited by
-
Metabolomics Reveals a Key Role for Fumarate in Mediating the Effects of NADPH Oxidase 4 in Diabetic Kidney Disease.J Am Soc Nephrol. 2016 Feb;27(2):466-81. doi: 10.1681/ASN.2015030302. Epub 2015 Jul 22. J Am Soc Nephrol. 2016. PMID: 26203118 Free PMC article.
-
Mapping of succinate dehydrogenase losses in 2258 epithelial neoplasms.Appl Immunohistochem Mol Morphol. 2014 Jan;22(1):31-6. doi: 10.1097/PAI.0b013e31828bfdd3. Appl Immunohistochem Mol Morphol. 2014. PMID: 23531856 Free PMC article.
-
The emerging role of fumarate as an oncometabolite.Front Oncol. 2012 Jul 31;2:85. doi: 10.3389/fonc.2012.00085. eCollection 2012. Front Oncol. 2012. PMID: 22866264 Free PMC article.
-
Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy.Ann Oncol. 2016 Sep;27(9):1794-9. doi: 10.1093/annonc/mdw228. Epub 2016 Jul 1. Ann Oncol. 2016. PMID: 27371698 Free PMC article. Clinical Trial.
-
Current and future treatments for malignant pheochromocytoma and sympathetic paraganglioma.Curr Oncol Rep. 2013 Aug;15(4):356-71. doi: 10.1007/s11912-013-0320-x. Curr Oncol Rep. 2013. PMID: 23674235 Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous