Abstract
BackgroundKetone bodies have both metabolic and epigenetic roles in cancer. In several studies, they showed an anti-cancer effect via inhibition of histone deacetylases; however, other studies observed faster tumour growth. The related molecule butyrate also inhibits growth of some cancer cells and accelerates it in others. This “butyrate paradox” is thought to be due to butyrate mediating histone acetylation and thus inhibiting cell proliferation in cancers that preferentially utilise glucose (the Warburg effect); whereas in cells that oxidise butyrate as a fuel, it fails to reach inhibitory concentrations and can stimulate growth.MethodsWe treated transgenic mice bearing spontaneous MMTV-NEU-NT mammary tumours with the ketone body β-hydroxybutyrate (β-OHB) and monitored tumour growth, metabolite concentrations and histone acetylation. In a cell line derived from these tumours, we also measured uptake of β-OHB and glucose, and lactate production, in the absence and presence of β-OHB.Resultsβ-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 β-OHB concentration within the treated tumours, 0.46 ± 0.05 μmol/g, had no effect on histone acetylation as shown by western blots. Cultured tumour cells incubated with 0.5 mM β-OHB showed β-OHB uptake that would be equivalent to 54% of glycolytic ATP phosphorylation and no significant change in glucose consumption or lactate production.ConclusionsThese results suggest that a β-OHB paradox may occur in these mammary tumours in a manner analogous to the butyrate paradox. At low β-OHB concentrations (<1 mM, as observed in our tumour model post-treatment), and in the absence of a Warburg effect, β-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.
Highlights
Ketone bodies have both metabolic and epigenetic roles in cancer
The results presented here indicate that daily ip injections of the ketone body β-OHB over a 3-week period significantly increased tumour growth rate in this autochthonous mouse mammary tumour model, no changes were seen in proliferative fraction, blood vessel density or apoptosis
The most extreme case we considered was culture in 10 mM β-OHB when the β-OHB uptake increased to 0.83 μmol β-OHB/106 cells/24 h and lactate output to 7.3 μmol/ 106 cells/24 h but the glucose consumption stayed at 4.3 μmol/106 cells/24 h (Fig. 7), implying that around 85% of the glucose uptake was consumed in glycolysis and that β-OHB oxidation would have provided about 50% more Adenosine triphosphate (ATP) than glycolysis (Table 2)
Summary
Ketone bodies have both metabolic and epigenetic roles in cancer. In several studies, they showed an anti-cancer effect via inhibition of histone deacetylases; other studies observed faster tumour growth. There has been renewed interest in cancer metabolism, with regard to the reprogramming of the metabolic networks within cancer tissue Understanding these metabolic perturbations could open a window for therapeutic intervention. The ketone bodies (KB), β-hydroxybutyrate (β-OHB) and acetoacetate are synthesised in the liver from acetylCoA and secreted into the blood, from which many tissues can take up and oxidatively metabolise them. Their main role is to provide an alternative substrate to glucose during prolonged starvation; in particular, due to their ability to cross the blood–brain barrier, they reduce the reliance of the brain on glucose. Ketogenic diets have been used in refractory epilepsy and have provided some benefit in hypoxic states, for prevention of muscle-wasting and in cancer [4]
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