Melatonin, a novel Sirt1 inhibitor, imparts antiproliferative effects against prostate cancer in vitro in culture and in vivo in TRAMP model
- 9 November 2010
- journal article
- Published by Wiley in Journal of Pineal Research
- Vol. 50 (2), 140-149
- https://doi.org/10.1111/j.1600-079x.2010.00823.x
Abstract
We recently demonstrated that Sirt1, a NAD+‐dependent histone deacetylase, was overexpressed in prostate cancer (PCa) and its inhibition resulted in a significant antiproliferative 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. Furthermore, disruption in melatonin production and circadian rhythmicity has been associated with aging. Here, we challenged our hypothesis that melatonin will impart antiproliferative 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 antiproliferative effects, suggesting that Sirt1 is a direct target of melatonin. Employing transgenic adenocarcinoma of mouse prostate (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 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.Keywords
This publication has 40 references indexed in Scilit:
- Circadian Control of the NAD + Salvage Pathway by CLOCK-SIRT1Science, 2009
- Role of Sirtuin Histone Deacetylase SIRT1 in Prostate CancerJournal of Biological Chemistry, 2009
- Combination of vitamin E and selenium causes an induction of apoptosis of human prostate cancer cells by enhancing Bax/Bcl‐2 ratioThe Prostate, 2008
- The NAD+-Dependent Deacetylase SIRT1 Modulates CLOCK-Mediated Chromatin Remodeling and Circadian ControlCell, 2008
- SIRT1 Regulates Circadian Clock Gene Expression through PER2 DeacetylationCell, 2008
- Chemopreventive Efficacy of Inositol Hexaphosphate against Prostate Tumor Growth and Progression in TRAMP MiceClinical Cancer Research, 2008
- Negative regulation of the deacetylase SIRT1 by DBC1Nature, 2008
- Immunocytochemical demonstration of day/night changes of clock gene protein levels in the murine adrenal gland: differences between melatonin‐proficient (C3H) and melatonin‐deficient (C57BL) miceJournal of Pineal Research, 2005
- Plasma insulin-like growth factor-1 and binding protein-3 and subsequent risk of prostate cancer in the PSA eraCancer Causes & Control, 2005
- Posttranslational Mechanisms Regulate the Mammalian Circadian ClockCell, 2001