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Review
. 2016 Nov:100:175-181.
doi: 10.1016/j.freeradbiomed.2016.04.025. Epub 2016 Apr 23.

Oncometabolites: Unconventional triggers of oncogenic signalling cascades

Marco Sciacovelli  1 , Christian Frezza  2
Affiliations
Review

Oncometabolites: Unconventional triggers of oncogenic signalling cascades

Marco Sciacovelli et al. Free Radic Biol Med. 2016 Nov.

Abstract

Cancer is a complex and heterogeneous disease thought to be caused by multiple genetic lesions. The recent finding that enzymes of the tricarboxylic acid (TCA) cycle are mutated in cancer rekindled the hypothesis that altered metabolism might also have a role in cellular transformation. Attempts to link mitochondrial dysfunction to cancer uncovered the unexpected role of small molecule metabolites, now known as oncometabolites, in tumorigenesis. In this review, we describe how oncometabolites can contribute to tumorigenesis. We propose that lesions of oncogenes and tumour suppressors are only one of the possible routes to tumorigenesis, which include accumulation of oncometabolites triggered by environmental cues.

Keywords: 2-Hydroxyglutarate; Cancer; FH; Fumarate; IDH; Mitochondria; Oncometabolites; SDH; Succinate.

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Figures

Fig. 1
Fig. 1
Schematic representation of overlapping features of tumours harbouring FH, SDH, and IDH mutations. Mutations in FH, SDH, and IDH lead to the accumulation of fumarate, succinate, and 2HG, respectively, activating a plethora of signalling cascades. Converging signatures, mainly mediated by aKGDD inhibition, include pseudohypoxia, histone and DNA hypermethylation. The colour of text indicates metabolic alterations (red), epigenetic alterations (blue), post-translational modifications (green) and other pro-tumorigenic alterations (black) elicited by these metabolites. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
An oncometabolic perspective of tumorigenesis. Schematic representation of how oncometabolite affect the process of tumorigenesis. The indicated oncometabolites can accumulate as a consequence of mutations of TCA cycle enzymes or environmental cues, such as hypoxia or hyperglycemia. These metabolites can act as proper oncogenic triggers and can drive transformation even in the absence of genetic alterations.
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