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G1/S 细胞周期调节剂介导昼夜节律紊乱对肿瘤生长的影响，并为定时抗癌治疗提供靶点。

G1/S cell cycle regulators mediate effects of circadian dysregulation on tumor growth and provide targets for timed anticancer treatment.

机构信息

Penn Chronobiology, Howard Hughes Medical Institute, Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

出版信息

PLoS Biol. 2019 Apr 30;17(4):e3000228. doi: 10.1371/journal.pbio.3000228. eCollection 2019 Apr.

DOI:10.1371/journal.pbio.3000228
PMID:31039152
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6490878/
Abstract

Circadian disruption has multiple pathological consequences, but the underlying mechanisms are largely unknown. To address such mechanisms, we subjected transformed cultured cells to chronic circadian desynchrony (CCD), mimicking a chronic jet-lag scheme, and assayed a range of cellular functions. The results indicated a specific circadian clock-dependent increase in cell proliferation. Transcriptome analysis revealed up-regulation of G1/S phase transition genes (myelocytomatosis oncogene cellular homolog [Myc], cyclin D1/3, chromatin licensing and DNA replication factor 1 [Cdt1]), concomitant with increased phosphorylation of the retinoblastoma (RB) protein by cyclin-dependent kinase (CDK) 4/6 and increased G1-S progression. Phospho-RB (Ser807/811) was found to oscillate in a circadian fashion and exhibit phase-shifted rhythms in circadian desynchronized cells. Consistent with circadian regulation, a CDK4/6 inhibitor approved for cancer treatment reduced growth of cultured cells and mouse tumors in a time-of-day-specific manner. Our study identifies a mechanism that underlies effects of circadian disruption on tumor growth and underscores the use of treatment timed to endogenous circadian rhythms.

摘要

昼夜节律紊乱会导致多种病理后果，但其中的机制在很大程度上尚不清楚。为了研究这些机制，我们让经过转化的培养细胞长期处于昼夜节律不同步（CCD）的状态，模拟慢性时差综合征，并检测多种细胞功能。结果表明，细胞增殖出现了特定的昼夜节律依赖性增加。转录组分析显示，G1/S 期转换基因（髓细胞瘤致癌基因细胞同源物[Myc]、细胞周期蛋白 D1/3、染色质许可和 DNA 复制因子 1 [Cdt1]）的上调，伴随着周期蛋白依赖性激酶（CDK）4/6 对视网膜母细胞瘤（RB）蛋白的磷酸化增加和 G1-S 进程的增加。磷酸化 RB（Ser807/811）呈昼夜节律性波动，并在昼夜节律不同步的细胞中出现节律相位偏移。与昼夜节律调节一致，一种用于癌症治疗的 CDK4/6 抑制剂以时间依赖性的方式减少了培养细胞和小鼠肿瘤的生长。本研究确定了昼夜节律紊乱对肿瘤生长影响的一种机制，并强调了根据内源性昼夜节律安排治疗时间的重要性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/6490878/59e9af89812f/pbio.3000228.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/6490878/f0d1f1e23da0/pbio.3000228.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/6490878/1c99e952cca7/pbio.3000228.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/6490878/186106f5b950/pbio.3000228.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/6490878/4d001882966f/pbio.3000228.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/6490878/f9ff5d27e1a3/pbio.3000228.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/6490878/59e9af89812f/pbio.3000228.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/6490878/f0d1f1e23da0/pbio.3000228.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/6490878/1c99e952cca7/pbio.3000228.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/6490878/186106f5b950/pbio.3000228.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/6490878/4d001882966f/pbio.3000228.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/6490878/f9ff5d27e1a3/pbio.3000228.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d80b/6490878/59e9af89812f/pbio.3000228.g006.jpg

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