Abstract 5478: Melatonin, a novel Sirt1 inhibitor, imparts anti-proliferative effects against PCa in vitro in cell culture and in vivo in transgenic adenocarcinoma of mouse prostate (TRAMP) model

Abstract

Abstract Prostate cancer (PCa) is a major age-related malignancy because an increase in age correlates with increased risk for developing this neoplasm. Recently, we have shown that Sirt1, a member of the NAD+ dependent histone deacetylase family of sirtuin proteins, was overexpressed in PCa cells and human PCa tissues compared to normal prostate cells and the adjacent normal prostate tissue, respectively. We also demonstrated that chemical inhibition or genetic knockdown of Sirt1 resulted in a significant inhibition in the growth and viability of human PCa cells while having no effect on normal human prostate epithelial cells (PrEC). Studies have suggested a link between the cellular metabolic function of Sirt1 and the circadian rhythm, and the disruption of circadian rhythm has been linked with an increased risk for some cancers. Interestingly, a decreased production of the pineal hormone melatonin, a known regulator of circadian rhythm, has been shown to cause deregulation in the circadian rhythm and an increase in susceptibility to cancer. Further, disruption in circadian rhythmicity has also been associated with aging. It has been reported that as an individual ages, the ability to produce melatonin at night is decreased and PCa patients have been reported to have decreased levels of melatonin. Here we tested the hypothesis that the circadian rhythm regulator melatonin will impart anti-proliferative response against PCa via inhibiting Sirt1. Our data demonstrated that melatonin treatments (high, low acute, low chronic doses) significantly inhibited Sirt1 protein and activity in vitro in multiple PCa cell lines (LNCaP, 22Rv1, DU145, and PC3). Melatonin-mediated Sirt1 inhibition was accompanied with a significant decrease in the proliferative capacity of PCa cells while having no effect on PrEC, as assessed by Trypan blue and anchorage-independent growth assays. Further, we found that overexpression of Sirt1 in PCa cells was able to partially rescue the cells from the anti-proliferative effects of melatonin, suggesting that Sirt1 is a direct target of the anti-proliferative effects of melatonin. Finally, employing male TRAMP mice, we found that oral administration of melatonin at human achievable doses significantly inhibited PCa growth. Melatonin treatment was found to result in a significant decrease in (i) prostate and genitourinary weight, (ii) serum IGF-1/IGFBP3 ratio, (iii) mRNA and protein levels of the proliferation markers (PCNA, Ki-67), and (iv) a down-regulation of Sirt1 in prostatic tissue. Our data identified melatonin as a novel inhibitor of Sirt1 and suggested that this pineal hormone can inhibit PCa growth via Sirt1 inhibition. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5478.