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.

中文翻译：

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β-羟基丁酸对自发性小鼠乳腺肿瘤的生长、代谢和整体组蛋白 H3 乙酰化的作用：β-羟基丁酸悖论的证据


背景酮体在癌症中具有代谢和表观遗传作用。在几项研究中，它们通过抑制组蛋白脱乙酰酶表现出抗癌作用。然而，其他研究观察到肿瘤生长更快。相关分子丁酸盐还可以抑制某些癌细胞的生长，并加速其他癌细胞的生长。这种“丁酸盐悖论”被认为是由于丁酸盐介导组蛋白乙酰化，从而抑制优先利用葡萄糖的癌症中的细胞增殖（瓦尔堡效应）；而在氧化丁酸作为燃料的细胞中，丁酸无法达到抑制浓度，可以刺激生长。方法我们用酮体β-羟基丁酸（β-OHB）治疗携带自发性MMTV-NEU-NT乳腺肿瘤的转基因小鼠，并监测肿瘤生长、代谢物浓度和组蛋白乙酰化。在源自这些肿瘤的细胞系中，我们还测量了在不存在和存在 β-OHB 的情况下对 β-OHB 和葡萄糖的摄取以及乳酸的产生。结果 β-OHB 给药加速了 MMTV-NEU-NT 肿瘤的生长，并且其代谢谱显示 ATP、谷氨酰胺、丝氨酸和胆碱相关代谢物显着增加。蛋白质印迹显示，治疗肿瘤内的 β-OHB 浓度为 0.46 ± 0.05 μmol/g，对组蛋白乙酰化没有影响。与 0.5 mM β-OHB 一起孵育的培养肿瘤细胞显示，β-OHB 的摄取相当于糖酵解 ATP 磷酸化的 54%，并且葡萄糖消耗或乳酸产生没有显着变化。结论这些结果表明，这些结果可能会出现 β-OHB 悖论。以类似于丁酸盐悖论的方式治疗乳腺肿瘤。 在低 β-OHB 浓度（<1 mM，如我们的肿瘤模型治疗后观察到的），并且在没有 Warburg 效应的情况下，β-OHB 被消耗，因此充当氧化能源而不是表观遗传因子。这可以解释治疗后肿瘤生长的增加、代谢特征以及对组蛋白 H3 乙酰化没有影响的原因。