Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer
- PMID:16892081
- DOI: 10.1038/sj.onc.1209594
Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer
Abstract
The phenomenon of enhanced glycolysis in tumours has been acknowledged for decades, but biochemical evidence to explain it is only just beginning to emerge. A significant hint as to the triggers and advantages of enhanced glycolysis in tumours was supplied by the recent discovery that succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tumour suppressors and which associated, for the first time, mitochondrial enzymes and their dysfunction with tumorigenesis. Further steps forward showed that the substrates of SDH and FH, succinate and fumarate, respectively, can mediate a 'metabolic signalling' pathway. Succinate or fumarate, which accumulate in mitochondria owing to the inactivation of SDH or FH, leak out to the cytosol, where they inhibit a family of prolyl hydroxylase enzymes (PHDs). Depending on the PHD inhibited, two newly recognized pathways that support tumour maintenance may ensue: affected cells become resistant to certain apoptotic signals and/or activate a pseudohypoxic response that enhances glycolysis and is conveyed by hypoxia-inducible factor.
Similar articles
- Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations.Pollard PJ, Brière JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP.Pollard PJ, et al.Hum Mol Genet. 2005 Aug 1;14(15):2231-9. doi: 10.1093/hmg/ddi227. Epub 2005 Jun 29.Hum Mol Genet. 2005.PMID:15987702
- Isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), fumarate hydratase (FH): three players for one phenotype in cancer?Laurenti G, Tennant DA.Laurenti G, et al.Biochem Soc Trans. 2016 Aug 15;44(4):1111-6. doi: 10.1042/BST20160099.Biochem Soc Trans. 2016.PMID:27528759Review.
- Mitochondrial tumour suppressors: a genetic and biochemical update.Gottlieb E, Tomlinson IP.Gottlieb E, et al.Nat Rev Cancer. 2005 Nov;5(11):857-66. doi: 10.1038/nrc1737.Nat Rev Cancer. 2005.PMID:16327764Review.
- Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors.Xiao M, Yang H, Xu W, Ma S, Lin H, Zhu H, Liu L, Liu Y, Yang C, Xu Y, Zhao S, Ye D, Xiong Y, Guan KL.Xiao M, et al.Genes Dev. 2012 Jun 15;26(12):1326-38. doi: 10.1101/gad.191056.112. Epub 2012 Jun 7.Genes Dev. 2012.PMID:22677546Free PMC article.
- The TCA cycle and tumorigenesis: the examples of fumarate hydratase and succinate dehydrogenase.Pollard PJ, Wortham NC, Tomlinson IP.Pollard PJ, et al.Ann Med. 2003;35(8):632-9. doi: 10.1080/07853890310018458.Ann Med. 2003.PMID:14708972Review.
Cited by
- Effect of Citric Acid Cycle Genetic Variants and Their Interactions with Obesity, Physical Activity and Energy Intake on the Risk of Colorectal Cancer: Results from a Nested Case-Control Study in the UK Biobank.Cho S, Song N, Choi JY, Shin A.Cho S, et al.Cancers (Basel). 2020 Oct 12;12(10):2939. doi: 10.3390/cancers12102939.Cancers (Basel). 2020.PMID:33053772Free PMC article.
- Identification of a Difluorinated Alkoxy Sulfonyl Chloride as a Novel Antitumor Agent for Hepatocellular Carcinoma through Activating Fumarate Hydratase Activity.Jin J, Liang X, Bi W, Liu R, Zhang S, He Y, Xie Q, Liu S, Xiao JC, Zhang P.Jin J, et al.Pharmaceuticals (Basel). 2023 Dec 8;16(12):1705. doi: 10.3390/ph16121705.Pharmaceuticals (Basel). 2023.PMID:38139831Free PMC article.
- Altered expression levels of IDH2 are involved in the development of colon cancer.Lv Q, Xing S, Li Z, Li J, Gong P, Xu X, Chang L, Jin X, Gao F, Li W, Zhang G, Yang J, Zhang X.Lv Q, et al.Exp Ther Med. 2012 Nov;4(5):801-806. doi: 10.3892/etm.2012.676. Epub 2012 Aug 20.Exp Ther Med. 2012.PMID:23226729Free PMC article.
- Conceptual framework for cutting the pancreatic cancer fuel supply.Le A, Rajeshkumar NV, Maitra A, Dang CV.Le A, et al.Clin Cancer Res. 2012 Aug 15;18(16):4285-90. doi: 10.1158/1078-0432.CCR-12-0041.Clin Cancer Res. 2012.PMID:22896695Free PMC article.Review.
- Metabolic rivalry: circadian homeostasis and tumorigenesis.Kinouchi K, Sassone-Corsi P.Kinouchi K, et al.Nat Rev Cancer. 2020 Nov;20(11):645-661. doi: 10.1038/s41568-020-0291-9. Epub 2020 Sep 7.Nat Rev Cancer. 2020.PMID:32895495Review.
Publication types
MeSH terms
Substances
Related information
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous