Crosstalk between metabolism and circadian rhythms is a fundamental building block of multicellular life, and disruption of this reciprocal communication could be relevant to disease. Here, we investigated whether maintenance of circadian rhythms depends on specific metabolic pathways, particularly in the context of cancer. We found that in adult mouse fibroblasts, ATP levels were a major contributor to signal from a clock gene luciferase reporter, although not necessarily to the strength of circadian cycling. In contrast, we identified significant metabolic control of circadian function across a series of pancreatic adenocarcinoma cell lines. Metabolic profiling of congenic tumor cell clones revealed substantial diversity among these lines that we used to identify clones to generate circadian reporter lines. We observed diverse circadian profiles among these lines that varied with their metabolic phenotype: The most hypometabolic line [exhibiting low levels of oxidative phosphorylation (OxPhos) and glycolysis] had the strongest rhythms, while the most hypermetabolic line had the weakest rhythms. Pharmacological enhancement of OxPhos decreased the amplitude of circadian oscillation in a subset of tumor cell lines. Strikingly, inhibition of OxPhos enhanced circadian rhythms only in the tumor cell line in which glycolysis was also low, thereby establishing a hypometabolic state. We further analyzed metabolic and circadian phenotypes across a panel of human patient-derived melanoma cell lines and observed a significant negative association between metabolic activity and circadian cycling strength. Together, these findings suggest that metabolic heterogeneity in cancer directly contributes to circadian function and that high levels of glycolysis or OxPhos independently disrupt circadian rhythms in these cells.

中文翻译：

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代谢亢进状态与小鼠和人癌细胞的昼夜节律破坏有关


新陈代谢和昼夜节律之间的串扰是多细胞生命的基本组成部分，这种互惠交流的破坏可能与疾病有关。在这里，我们研究了昼夜节律的维持是否取决于特定的代谢途径，尤其是在癌症的情况下。我们发现，在成年小鼠成纤维细胞中，ATP 水平是时钟基因荧光素酶报告基因信号的主要贡献者，尽管不一定与昼夜节律周期的强度有关。相比之下，我们在一系列胰腺癌细胞系中发现了对昼夜节律功能的显着代谢控制。同源肿瘤细胞克隆的代谢分析揭示了这些细胞系之间的显著多样性，我们用这些细胞系来识别克隆以产生昼夜节律报告基因系。我们在这些谱系中观察到不同的昼夜节律谱，这些谱系随其代谢表型而变化：代谢最低调的谱系 [表现出低水平的氧化磷酸化 （OxPhos） 和糖酵解] 具有最强的节律，而最代谢亢进的谱系具有最弱的节律。OxPhos 的药理学增强降低了肿瘤细胞系亚群中昼夜节律振荡的幅度。引人注目的是，抑制 OxPhos 仅在糖酵解也很低的肿瘤细胞系中增强昼夜节律，从而建立代谢减退状态。我们进一步分析了一组人类患者来源的黑色素瘤细胞系的代谢和昼夜节律表型，并观察到代谢活动与昼夜节律周期强度之间存在显着的负相关。 总之，这些发现表明癌症中的代谢异质性直接影响昼夜节律，并且高水平的糖酵解或 OxPhos 独立破坏了这些细胞的昼夜节律。