Warburg tumours and the mechanisms of mitochondrial tumour suppressor genes. Barking up the right tree?

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The past decade has seen a revival of interest in the metabolic adaptations of tumours, named for their original discoverer, Otto Warburg. Warburg reported a high rate of glycolysis in tumours, and a concurrent defect in mitochondrial respiration. The rediscovery of Warburg's hypothesis coincided with the discovery of mitochondrial tumours suppressor genes that may conform to Warburg's hypothesis. Succinate dehydrogenase and fumarate hydratase are mitochondrial proteins of the TCA cycle and the respiratory chain and when mutated lead to tumours of the nervous system known as paragangliomas and pheochromocytomas, and in the case of fumarate hydratase, cutaneous and uterine leiomyomas and renal cell cancer. Recently a novel mitochondrial protein, SDHAF2 (SDH5), was also shown to be a paraganglioma-related tumour suppressor gene. Another mitochondrial and TCA cycle-related protein, isocitrate dehydrogenase 2 is, together with IDH1, frequently mutated in the brain tumour glioblastoma.

There are currently many competing hypotheses on the role of these genes in tumourigenesis, but frequent themes are the stabilization of hypoxia inducible factor 1 and upregulation of genes involved in angiogenesis, glucose transport and glycolysis. Other postulated mechanisms include the inhibition of developmental apoptosis, altered gene expression due to histone deregulation and the acquisition of novel catalytic properties. Here we discuss these diverse hypotheses and highlight very recent findings on the possible effects of IDH gene mutations.

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      Citation Excerpt :

      Mutations in TCA related genes fumaratehydratase (FH), succinate dehydrogenase (SDH), and isocitrate dehydrogenase (IDH) 1 and 2 result in the generation and subsequent accumulation of their respective oncogenic metabolites. Importantly, mutant forms of these enzymes induce the activation of HIF [21]. Taken together, altered cancer metabolism is a result of complex interplays between the metabolic and non-metabolic proteins that converge to produce a cellular phenotype that is more inclined towards aerobic glycolysis for energy and proliferation purposes.

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