Melatonin resynchronizes dysregulated circadian rhythm circuitry in human prostate cancer cells.
Melatonin resynchronizes dysregulated circadian rhythm circuitry in human prostate cancer cells.
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DOI：
10.1111/j.1600-079x.2010.00767.x
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发表时间：
2010-08
影响因子：
10.3
通讯作者：
Ahmad N
中科院分区：
文献类型：
--
作者：
Jung-Hynes B;Huang W;Reiter RJ;Ahmad N
前列腺癌（PCa）是一种主要的与年龄相关的恶性肿瘤，随着年龄的增长，患这种肿瘤的风险增加。同样，昼夜节律的改变也与人口老龄化和癌症风险有关。已知松果体褪黑激素调节昼夜节律，昼夜节律受一组核心基因的控制：周期1,2,3 (Per 1 - 3)；隐花色素1,2 (Cry 1,2)；时钟，和Bmal 1,2。褪黑素水平已被证明在癌症患者中降低，外源性褪黑素对某些癌症具有抗增殖作用。在这项研究中，我们挑战了褪黑素通过解除管制的核心时钟电路的再同步而赋予前列腺癌抗增殖作用的假设。我们发现，与正常前列腺细胞相比，PCa细胞中的Clock和Per2蛋白水平下调，而Bmal1蛋白水平上调。此外，通过对含有人体组织的微阵列进行自动定量分析，我们发现，与良性组织相比，前列腺癌和其他增生性前列腺疾病的Clock和Per2水平下调，而Bmal1水平上调。Per2的过表达会导致前列腺癌细胞生长和生存能力的显著下降。有趣的是，褪黑素治疗导致PCa细胞中Per2和Clock的增加和Bmal1的减少。此外，褪黑激素治疗导致振荡昼夜节律基因（Dbp和Per2）的重新同步。我们的数据支持我们的假设，并建议褪黑激素作为治疗前列腺癌和其他年龄相关恶性肿瘤的药物应该进行彻底的研究。
Prostate cancer (PCa) is a major age-related malignancy as increasing age correlates with increased risk for developing this neoplasm. Similarly, alterations in circadian rhythms have also been associated with the aging population and cancer risk. The pineal hormone melatonin is known to regulate circadian rhythms, which are under the control of a core set of genes: Period 1, 2, 3 (Per 1 – 3); Cryptochrome 1, 2 (Cry 1, 2); Clock, and Bmal 1, 2. Melatonin levels have been shown to decrease in cancer patients and exogenous melatonin exhibits anti-proliferative effects against certain cancers. In this study, we challenged the hypothesis that melatonin imparts anti-proliferative effects in prostate cancer via resynchronization of deregulated core clock circuitry. We found that Clock and Per2 protein levels were downregulated whereas Bmal1 protein levels were upregulated in PCa cells, compared to normal prostate cells. Additionally, employing automated quantitative analysis of a microarray containing human tissues, we found that compared to benign tissues, Clock and Per2 levels were downregulated whereas Bmal1 levels were upregulated in PCa and other proliferative prostatic conditions. Overexpression of Per2 was found to result in a significant loss of PCa cell growth and viability. Interestingly, melatonin treatment resulted in an increase in Per2 and Clock and a reduction in Bmal1 in PCa cells. Further, melatonin treatment resulted in a resynchronization of oscillatory circadian rhythm genes (Dbp and Per2). Our data support our hypothesis and suggest that melatonin should be thoroughly investigated as an agent for the management of PCa and other age-related malignancies.