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. 2012 Jul 31:2:85.
doi: 10.3389/fonc.2012.00085. eCollection 2012.

"V体育平台登录" The emerging role of fumarate as an oncometabolite

Ming Yang  1 , Tomoyoshi Soga, Patrick J Pollard, Julie Adam
Affiliations

The emerging role of fumarate as an oncometabolite

Ming Yang et al. Front Oncol. .

VSports注册入口 - Abstract

The drive to understand how altered cellular metabolism and cancer are linked has caused a paradigm shift in the focus of cancer research. The discovery of a mutated metabolic enzyme, isocitrate dehydrogenase 1, that leads to accumulation of the oncometabolite 2-hydroxyglutarate, provided significant direct evidence that dysfunctional metabolism plays an important role in oncogenesis. Striking parallels exist with the Krebs cycle enzyme fumarate hydratase (FH), a tumor suppressor, whose mutation is associated with the development of leiomyomata, renal cysts, and tumors. Loss of FH enzymatic activity results in accumulation of intracellular fumarate which has been proposed to act as a competitive inhibitor of 2-oxoglutarate-dependent oxygenases including the hypoxia-inducible factor (HIF) hydroxylases, thus activating oncogenic HIF pathways VSports手机版. Interestingly, our studies have questioned the role of HIF and have highlighted other candidate mechanisms, in particular the non-enzymatic modification of cysteine residues (succination) that could lead to disruption or loss of protein functions, dysfunctional cell metabolism and cell signaling. Here, we discuss the evidence for proposing fumarate as an onco-metabolite. .

Keywords: dysregulated metabolism; fumarate; mitochondrial dysfunction; oncometabolite; succination. V体育安卓版.

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Figures

FIGURE 1
FIGURE 1
Consequences of elevated cellular fumarate. Loss of fumarate hydratase enzyme activity results in intracellular accumulation of fumarate with multiple diverse consequences. However, it remains to be determined whether some, or all of these, or indeed other as yet uncovered pathways, lead directly to oncogenesis. Dysregulated metabolism possibly linked to reductive carboxylation may both result from elevated fumarate and is certainly a cause of the elevated fumarate. Mitochondrial dysfunction is a feature of both altered metabolism and possibly high fumarate levels; but whether it is a contributing factor in oncogenesis needs to be determined and if autophagy leads to increased availability of nutrients for the cell. Fumarate has been shown to act as a competitive inhibitor of members of the 2-oxoglutarate-dependent oxygenase superfamily including the histone demethylase enzymes (HDMs), TET proteins and hypoxia-inducible factor (HIF) hydroxylases, thus activating oncogenic HIF pathways. However, further investigation is required to ascertain whether fumarate initiates oncogenesis via all, or any, of these routes. Succination of cysteine residues that could lead to disruption or loss of protein functions, dysfunctional cell metabolism and cell signaling offers a novel and promising route to link fumarate and oncogenesis directly. The benefits of fumarate proposed in activating a DNA damage response need to be addressed further, while the cytoprotective role proposed for fumarate in cardiac cells by diverting amino acids into the Krebs cycle and activating the Nrf2 antioxidant pathway suggests that different cell types may have different response strategies.
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