Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA.
J Pineal Res. 2010 Aug;49(1):60-8. doi: 10.1111/j.1600-079X.2010.00767.x. Epub 2010 May 27.
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 is 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 patients with cancer and exogenous melatonin exhibits antiproliferative effects against certain cancers. In this study, we challenged the hypothesis that melatonin imparts antiproliferative 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.
前列腺癌（PCa）是一种主要的与年龄相关的恶性肿瘤，因为随着年龄的增长，患这种肿瘤的风险也会增加。同样，昼夜节律的改变也与老年人口和癌症风险有关。松果体激素褪黑素已知可以调节昼夜节律，而昼夜节律受一组核心基因的控制：Period 1、2、3（Per1-3）；Cryptochrome 1、2（Cry1、2）；Clock 和 Bmal 1、2。已经表明，癌症患者的褪黑素水平下降，外源性褪黑素对某些癌症具有抗增殖作用。在这项研究中，我们假设褪黑素通过重新同步失调的核心时钟电路来赋予前列腺癌抗增殖作用。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，通过对包含人类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，Clock 和 Per2 水平在 PCa 和其他增殖性前列腺疾病中下调，而 Bmal1 水平上调。发现过表达 Per2 会导致 PCa 细胞生长和活力显著丧失。有趣的是，褪黑素处理导致 PCa 细胞中 Per2 和 Clock 增加，而 Bmal1 减少。此外，褪黑素处理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，并表明褪黑素应该作为治疗 PCa 和其他与年龄相关的恶性肿瘤的药物进行深入研究。
