超代谢状态与小鼠和人类癌细胞中昼夜节律扰乱有关
Daniel Maxim Iascone1, Xue Zhang2,3, Patricia Brafford2,3
1HHMI, Chronobiology and Sleep Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
概括
破坏细胞代谢会影响昼夜节律,特别是在癌症中. 降低代谢活动,如糖解和氧化酸化,在癌细胞中加强这些节律,这表明代谢和疾病之间存在联系.
科学领域:
- 细胞生物学 细胞生物学
- 代谢途径 代谢途径
- 癌症生物学 癌症生物学
背景情况:
- 代谢和昼夜节律之间的相互作用对多细胞生物来说至关重要.
- 这种沟通中断与各种疾病有关,包括癌症.
研究的目的:
- 研究维持昼夜节律对癌症特定代谢途径的依赖性.
- 探索胰腺腺癌和黑色素瘤细胞系中的代谢表型和昼夜功能之间的关系.
主要方法:
- 利用ATP水平作为小鼠纤维细胞中的钟基因光酶记者信号.
- 在胰腺腺癌细胞克隆上进行了代谢分析,以识别不同的代谢表型.
- 从这些克隆中生成昼夜记者线,以评估昼夜概况.
- 在人类患者衍生的黑色素瘤细胞系中检查了代谢和昼夜表型.
主要成果:
- 在小鼠纤维细胞中,ATP水平影响了记者信号,但不一定影响昼夜循环的强度.
- 胰腺癌细胞系表现出与其代谢状态相关的各种昼夜特征;低代谢细胞系比高代谢细胞系有更强的节律.
- 氧化酸化 (OxPhos) 的药理学操纵影响了昼夜振荡幅度.
- 抑制OxPhos仅在低糖解的细胞系中增强了昼夜节律,诱导了低代谢状态.
- 在黑色素瘤细胞系中观察到代谢活动和昼夜循环强度之间的负相关性.
结论:
- 癌症中的代谢异质性直接影响昼夜功能.
- 高水平的糖解或OxPhos独立地破坏癌细胞中的昼夜节律.
- 准代谢途径可能为癌症治疗中调节昼夜节律提供策略.
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