Mitochondrial tumour suppressors: A genetic and biochemical link between metabolism and cancer

Author: E. Gottlieb
Submitted: Thursday 10th of February 2011 09:41:13 AM
Submitted by: egf
Language: English
Content type: Learning resource
Educational levels: expert, qc3

Abstract

Both succinate dehydrogenase (SDH) and fumarate hydratase (FH) are TCA cycle enzymes that convert succinate to fumarate and fumarate to malate, respectively. SDH is also a functional member (complex II) of the Electron Transport Chain (ETC). Surprisingly, although SDH and FH are „housekeeping genes‟ with key bioenergetic roles, germline mutations in these genes cause cancer. We demonstrated that succinate, a TCA cycle metabolite (an SDH substrate), functions as an intracellular messenger between mitochondria and the cytosol. Succinate, which accumulates in mitochondria due to the inactivation of SDH, leaks out to the cytosol, where it inhibits the enzymatic machinery of oxygen sensing, mediated by a family of α-ketoglutarate-dependent Prolyl Hydroxylase enzymes (PHD). PHD inhibition by succinate triggers the accumulation and activation of the hypoxia inducible factor (HIF) in the nucleus and the pseudohypoxic response that enhances tumour vascularization and glycolysis. These and other independent studies collectively suggested that PHD inhibition and pseudohypoxia are important factors that link mitochondrial tumour suppressors and cancer. This observation received further support recently from the fact that PHD2 was genetically identified as a likely tumour suppressor. The inhibition of PHD by succinate is achieved by a product inhibition mechanism, given that PHD hydroxylates its targets while utilizing α-ketoglutarate as a substrate and producing succinate. We further characterized the nature of succinate-mediated inhibition of PHD and showed that this inhibition is competitive in nature. Therefore, the ratio, rather than the absolute concentrations, of α-ketoglutarate to succinate or fumarate in cells critically affect PHD activity and HIF activity. We designed and synthesised cell-permeating α-ketoglutarate esters that are hydrolyzed in the cytosol by esterases. These compounds support PHD activity thereby lowering HIF levels and activity in SDH deficient cells. Our study suggests that well designed α-ketoglutarate derivatives may have therapeutic potential in the treatment of tumours with functional down-regulation or mutations of SDH or FH, where it could restore normal PHD activity and low levels of HIF.

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abstract Mitochondrial_tumour_suppressors_a_genetic_and_biochemical_link_between_metabolism_and_cancer_Gottlieb_5120.ppt

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E. Gottlieb. Mitochondrial tumour suppressors: A genetic and biochemical link between metabolism and cancer. EUROGENE portal. February 2011. online: http://eurogene.open.ac.uk/content/mitochondrial-tumour-suppressors-genetic-and-biochemical-link-between-metabolism-and-cancer

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