Melatonin, a novel Sirt1 inhibitor, imparts antiproliferative effects against prostate cancer in vitro in culture and in vivo in TRAMP model.
Melatonin, a novel Sirt1 inhibitor, imparts antiproliferative effects against prostate cancer in vitro in culture and in vivo in TRAMP model.
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DOI：
10.1111/j.1600-079x.2010.00823.x
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发表时间：
2011-03
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;Schmit TL;Reagan-Shaw SR;Siddiqui IA;Mukhtar H;Ahmad N
我们最近证明Sirt1，一种NAD+依赖性组蛋白去乙酰化酶，在前列腺癌（PCa）中过度表达，其抑制导致人类PCa细胞显著的抗增殖反应。研究表明Sirt1与昼夜节律之间存在联系，而昼夜节律的破坏与癌症有关。有趣的是，松果体褪黑素的减少已被证明会解除对昼夜节律机制的调节，增加患癌症的风险。此外，褪黑激素的产生和昼夜节律的紊乱与衰老有关。在这里，我们挑战了我们的假设，即褪黑激素将通过抑制Sirt1对PCa产生抗增殖反应。在体外实验中，我们发现褪黑激素显著抑制了多种人类PCa细胞系的Sirt1蛋白及其活性，褪黑激素介导的Sirt1抑制伴随着PCa细胞增殖潜力的显著降低，而正常细胞则没有。被迫过表达Sirt1部分地使PCa细胞免受褪黑激素的抗增殖作用，这表明Sirt1是褪黑激素的直接靶点。通过对TRAMP小鼠的研究，我们还证明了口服褪黑素，在人类可达到的剂量下，显著抑制前列腺癌的肿瘤发生，表现为(i)前列腺和泌尿生殖系统（GU）重量的降低，（ii）血清胰岛素样生长因子-1 (IGF-1)/ igf结合蛋白-3 （IGFBP3）比例的降低，（iii）增殖标志物（PCNA, Ki-67） mRNA和蛋白水平的降低。这种抗前列腺癌反应伴随着Sirt1的显著降低。我们的数据表明褪黑激素是Sirt1的一种新型抑制剂，并表明褪黑激素可以通过抑制Sirt1来抑制PCa的生长。
We recently demonstrated that Sirt1, a NAD+ dependent histone deacetylase, was overexpressed in prostate cancer (PCa) and its inhibition resulted in a significant anti-proliferative response in human PCa cells. Studies have suggested a link between Sirt1 and circadian rhythms, the disruption of which has been linked to cancer. Interestingly, a decreased production of the pineal melatonin has been shown to deregulate the circadian rhythm machinery and increase cancer risk. Further, disruption in melatonin production and circadian rhythmicity has been associated with aging. Here, we challenged our hypothesis that melatonin will impart anti-proliferative response against PCa via inhibiting Sirt1. We demonstrated that melatonin significantly inhibited Sirt1 protein and activity in vitro in multiple human PCa cell lines and melatonin-mediated Sirt1 inhibition was accompanied with a significant decrease in the proliferative potential of PCa cells, but not of normal cells. Forced overexpression of Sirt1 partially rescued the PCa cells from melatonin’s anti-proliferative effects, suggesting that Sirt1 is a direct target of melatonin. Employing TRAMP mice, we also demonstrated that oral administration of melatonin, at human achievable doses, significantly inhibited PCa tumorigenesis as shown by decreases in (i) prostate and genitourinary (GU) weight, (ii) serum insulin-like growth factor-1 (IGF-1)/IGF-binding protein-3 (IGFBP3) ratio, (iii) mRNA and protein levels of the proliferation markers (PCNA, Ki-67). This anti-PCa response was accompanied with a significant decrease in Sirt1 in TRAMP prostate. Our data identified melatonin as a novel inhibitor of Sirt1 and suggest that melatonin can inhibit PCa growth via Sirt1 inhibition.