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, because of modifications in various core clock components, have also been associated with the aging population and cancer risk. The pineal hormone melatonin is known to regulate circadian rhythm, which is under the control of a core set of genes: Per-, Clock- and Bmal-family members. The circulating serum levels of melatonin have been shown to decrease in patients with cancer including PCa. Interestingly, melatonin has been shown to have anti-proliferative effects in certain cancers. We have recently found that melatonin imparts anti-proliferative effects in vitro and in vivo via inhibiting Sirt1 that is a class III histone deacetylase and involved in the regulation of aging and several other metabolic processed. In this study, we challenged the hypothesis that melatonin imparts anti-proliferative effects in prostate cancer via resynchronization of deregulated core clock circuitry at the cellular level. First, we determined if the core clock genes circuitry is disrupted in PCa. Interestingly, we found that Clock and Per2 protein levels were downregulated whereas Bmal1 protein levels were up regulated in PCa cells (LNCaP, 22R 1, DU145, PC3), compared to normal prostate epithelial cells as assessed by Western blot analysis. Further, we employed the automated quantitative analysis (AQUA) system to asses the levels of Clock, Per2 and Bmal1 in a tissue microarray (TMA) containing clinical specimens of benign prostate hyperplasia (BPH), high-grade intraepithelial neoplasias (HGPIN), localized PCa, aggressive PCa with metastases as well as benign prostate tissue. We found that compared to benign tissues, in all proliferative prostate diseases Clock and Per2 levels were downregulated whereas Bmal1 levels were up regulated. In addition, a forced over-expression of Per2 was found to result in a significant loss of viability of PCa cells. Further, we found that melatonin (1mM and 2mM; 48 h) treatment causes an increase in Per2 and Clock and decrease in Bmal1 (at the protein and mRNA levels) in human PCa cells. Furthermore, as shown by the COSOPT algorithm, we found that melatonin treatment resulted in a resynchronization of oscillatory circadian rhythm genes (Dbp and Per2) while having no effect on non-oscillatory genes. 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.

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 LB-16.