HHMI, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2024 Jul 23;121(30):e2319782121. doi: 10.1073/pnas.2319782121. Epub 2024 Jul 15.
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.
代谢与昼夜节律的相互作用是多细胞生命的基本组成部分，这种相互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依赖于特定的代谢途径，特别是在癌症的背景下。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，尽管不一定是昼夜循环的强度。相比之下，我们在一系列胰腺腺癌细胞系中发现了昼夜节律功能的显著代谢控制。对同源肿瘤细胞克隆的代谢谱分析揭示了这些细胞系之间存在显著的多样性，我们利用这些多样性来鉴定克隆以生成昼夜节律报告基因系。我们观察到这些细胞系之间存在不同的昼夜节律模式，这些模式因代谢表型而异：代谢最低的细胞系（表现出低水平的氧化磷酸化和糖酵解）具有最强的节律，而代谢最高的细胞系具有最弱的节律。氧化磷酸化的药理学增强在一部分肿瘤细胞系中降低了昼夜振荡的幅度。引人注目的是，氧化磷酸化的抑制仅在糖酵解也较低的肿瘤细胞系中增强了昼夜节律，从而建立了低代谢状态。我们进一步分析了一组人源肿瘤细胞系的代谢和昼夜节律表型，观察到代谢活性和昼夜节律强度之间存在显著的负相关。综上所述，这些发现表明，癌症中的代谢异质性直接影响昼夜节律功能，高水平的糖酵解或氧化磷酸化独立地破坏这些细胞的昼夜节律。
