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Background Ketone bodies have both metabolic and epigenetic roles in cancer.

Background Ketone bodies have both metabolic and epigenetic roles in cancer. (-OHB) and monitored tumour growth, metabolite concentrations and histone acetylation. In a cell line derived from these tumours, we also measured uptake of -OHB and glucose, and lactate production, in the absence and presence of -OHB. Results -OHB administration accelerated growth of MMTV-NEU-NT tumours, and their metabolic profile showed significant increases in ATP, glutamine, serine and choline-related metabolites. The -OHB concentration within the treated tumours, 0.46??0.05?mol/g, had no effect on histone acetylation as shown by western blots. Cultured tumour cells incubated with 0.5?mM -OHB showed -OHB uptake that would be equivalent to 54% of glycolytic ATP phosphorylation and no significant change in glucose consumption or lactate production. Conclusions These results suggest that a -OHB paradox may occur in these mammary tumours in a manner analogous to the butyrate paradox. At buy 88901-45-5 low -OHB concentrations (<1?mM, as observed in our tumour model post-treatment), and in the absence of a Warburg effect, -OHB is consumed and thus acts as an oxidative energy source and not as an epigenetic factor. This would explain the increase in tumour growth after treatment, the metabolic profiles and the absence of an effect on histone H3 acetylation. the growth of cancers [8C10]. On the anti-cancer side, studies on orthotopically implanted mouse astrocytomas have reported that malignant brain tumours are potentially manageable with dietary therapies that reduce glucose and elevate KB, since these brain tumours lack metabolic versatility and are dependent largely on glucose for energy [5]. More recent studies have evaluated the anti-cancer and anti-cachectic properties of KB in cultured pancreatic tumour cells as well as Mdk the effect of ketogenic diets on tumour burden and cachexia in orthotopically implanted models of pancreatic cancer [7]. The authors proposed that KB-induced metabolomic reprogramming by ketogenic diets suppresses cancer and cancer-induced cachexia. In another study, Poff et al. [3] showed that dietary administration of ketone precursors extended the survival time of mice with metastatic cancer by 50C70%. In contrast, other studies on breast cancer have shown that KB utilisation drives tumour growth and metastasis [8C10]. One of these papers demonstrated that KB, when administered systemically to animals bearing a breast tumour xenograft, promoted the growth of those tumours with no significant buy 88901-45-5 increase in angiogenesis and with a transcriptional shift towards oxidative mitochondrial metabolism in cancer epithelial cells relative to adjacent stromal cells [8]. In addition to their metabolic role, KB are also integrated into buy 88901-45-5 the regulation of epigenetic states and transcription, thus providing potential mechanisms that link cellular energy metabolism and regulation of gene expression via chromatin modification [11, 12]. -OHB, for instance, is an endogenous inhibitor of the histone deacetylases (HDACs; also termed lysine deacetylases) which remove acetyl epigenetic marks from histones and other proteins that interact with DNA. Acetyl-CoA, in addition to being the substrate for synthesis of KBs, is also the co-factor of the histone acetyltransferase enzymes (HATs) that incorporate acetyl groups into histones [13]. Deregulation of histone acetylation results in abnormal expression profiles of genes involved in cell proliferation and differentiation and is associated with malignancy [14]. Butyrate, closely related to -OHB, has been an essential agent for determining the role of histone acetylation in chromatin function, and observations that butyrate-treated cells show histone hyperacetylation led to the discovery that butyrate inhibits HDAC activity [15]. Its role in linking energy metabolism with epigenetics has been reported by Donohoe et al. [16]. Butyrate is a short-chain fatty acid produced by fermentation of dietary fibre in the colon, where it is metabolised oxidatively and functions as a primary energy source for colonocytes. Notably, butyrate has been shown to have growth-inhibitory effects in cancerous cells but either no effect or stimulation of growth in non-cancerous cells. These opposing effects on normal versus cancerous cells have been termed the butyrate paradox (reviewed by Lupton 2004) [17]. It is thought that this paradox results from epigenetic effects of butyrate on the two cell types. Donohoe.