Melatonin as a novel Sirt1 inhibitor for the management of prostate cancer

描述(申请人提供)：前列腺癌(PCa)是美国和其他几个发达国家男性最常见的恶性肿瘤。随着年龄的增长，男性发生前列腺癌的几率显著增加；因此，确定衰老机制与前列腺癌之间的因果关系是很重要的。在最近的一项研究中，我们发现Sirti是一种与长寿相关的组蛋白去乙酰化酶，在PCa细胞和组织中过表达，它的抑制会导致PCa细胞生长和活力的下降以及衰老的增加。此外，我们最近令人兴奋的初步数据表明，褪黑素是一种松果体激素，也是癌症患者广泛使用的补充剂，是一种有效的Sirti抑制剂。人体合成褪黑激素表现出昼夜节律，这种昼夜节律是由位于下丘脑的生物钟产生的。研究表明，褪黑素在多种实验模型中具有化学预防、抑癌和肿瘤抑制作用。此外，褪黑素有可能在辅助环境下提高化疗的疗效并减少副作用。体外研究也表明，褪黑素对人前列腺癌细胞具有抗增殖作用。重要的是，Sirti被发现是几个核心时钟基因(Bmall、Rory、PER2和Cryl)的昼夜节律转录所必需的，这表明Sirti将细胞新陈代谢与昼夜节律的核心时钟电路联系起来。褪黑素已经被证明控制着各种时钟基因，这些基因最近被认为与癌症有关。这一建议利用了这些新的观察结果，本申请中提出的工作的中心假设是褪黑素将通过Sirti抑制介导的昼夜节律核心时钟电路的调制来传递抗增殖和化学预防前列腺癌的效果。现已提出以下具体目标：1)建立褪黑素在人前列腺癌细胞中的抗增殖作用与Sirti之间的因果关系；2)确定昼夜节律基因是否参与褪黑素在前列腺癌细胞中抗增殖作用的机制；以及3)在体内通过Sirti抑制介导的时钟基因调控模拟人类疾病的特征的转基因小鼠前列腺癌(TRAMP)中，确定褪黑素是否会提供抗增殖和/或化学预防作用。我们相信，这项研究的成功完成将建立一)褪黑素(一种广泛使用的CAM方法)对抗前列腺癌的潜力，以及二)褪黑素生物学效应的新的分子机制(S)。这可能有助于为PCA的管理设计新的战略。

DESCRIPTION (provided by applicant): Prostate Cancer (PCa) is the most commonly occurring malignancy in men in the USA and several other developed countries. A man's chance of developing PCa significantly increases with increasing age; therefore, it is important to define the causal connection between mechanisms of aging and PCa. In a recent study, we have found Sirti, a longevity-associated histone deacetylase, is overexpressed in PCa cells and tissues and its inhibition causes a decrease in cell growth and viability and increase in senescence in PCa cells. Further, our recent exciting preliminary data has shown that melatonin, a pineal hormone and a widely used supplement among cancer patients, is a potent inhibitor of Sirti. Melatonin synthesis by the human body displays a circadian rhythm that is generated by a circadian clock located in the hypothalamus. Studies have shown that melatonin possesses chemopreventive, oncostatic and tumor inhibitory effects in a variety of experimental models. Further, melatonin has a potential to increase the efficacy and decrease the side effects of chemotherapy in adjuvant settings. In vitro studies have also indicated that melatonin possesses antiproliferative effects against human PCa cells. Importantly Sirti has been found to be required for circadian transcription of several core clock genes (Bmall, Rory, Per2, and Cryl) suggesting that Sirti connects cellular metabolism to the circadian core clockwork circuitry. Melatonin has been shown to control a variety of clock genes which have recently been linked to cancer. This proposal capitalizes on these novel observations and the central hypothesis of the work proposed in this application is that melatonin will impart anti-proliferative as well as chemopreventive effects against prostate cancer via Sirti inhibition-mediated modulations in circadian core clockwork circuitry. The following specific aims are proposed; 1) To establish a cause-and-effect association between the anti-proliferative effects of melatonin and Sirti in human PCa cells; 2) To determine the involvement of circadian rhythm genes as a mechanism of the anti-proliferative effects of melatonin in PCa cells; and 3) To determine if melatonin will impart anti-proliferative and/or chemopreventive effects against PCa via Sirti inhibition-mediated modulations in clock genes in vivo in transgenic adenocarcinoma mouse prostate (TRAMP) mice, which mimics the features of human disease. We believe that successful completion of this proposal will establish i) the potential of melatonin (a widely used CAM approach) against PCa, and ii) a novel molecular mechanism(s) of the biological effects of melatonin. This may help in designing novel strategies for the management of PCa.