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Melatonin resynchronizes dysregulated circadian rhythm circuitry in human prostate cancer cells.

ABSTRACT: 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 have also been associated with the aging population and cancer risk. The pineal hormone melatonin is known to regulate circadian rhythms, which is under the control of a core set of genes: Period 1, 2, 3 (Per 1-3); Cryptochrome 1, 2 (Cry 1, 2); Clock, and Bmal 1, 2. Melatonin levels have been shown to decrease in patients with cancer and exogenous melatonin exhibits antiproliferative effects against certain cancers. In this study, we challenged the hypothesis that melatonin imparts antiproliferative effects in prostate cancer via resynchronization of deregulated core clock circuitry. We found that Clock and Per2 protein levels were downregulated whereas Bmal1 protein levels were upregulated in PCa cells, compared to normal prostate cells. Additionally, employing automated quantitative analysis of a microarray containing human tissues, we found that compared to benign tissues, Clock and Per2 levels were downregulated, whereas Bmal1 levels were upregulated in PCa and other proliferative prostatic conditions. Overexpression of Per2 was found to result in a significant loss of PCa cell growth and viability. Interestingly, melatonin treatment resulted in an increase in Per2 and Clock and a reduction in Bmal1 in PCa cells. Further, melatonin treatment resulted in a resynchronization of oscillatory circadian rhythm genes (Dbp and Per2). 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.

SUBMITTER: Jung-Hynes B

PROVIDER: S-EPMC3158680 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Melatonin resynchronizes dysregulated circadian rhythm circuitry in human prostate cancer cells.

Jung-Hynes Brittney B Huang Wei W Reiter Russel J RJ Ahmad Nihal N

Journal of pineal research 20100527 1

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 have also been associated with the aging population and cancer risk. The pineal hormone melatonin is known to regulate circadian rhythms, which is under the control of a core set of genes: Period 1, 2, 3 (Per 1-3); Cryptochrome 1, 2 (Cry 1, 2); Clock, and Bmal 1, 2. Melatonin levels have been shown to decrease in patien ...[more]

PMID: 20524973

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Project description:Gut hormones are not only able to regulate digestive, absorptive, and immune mechanisms of the intestine through biological rhythms, but impact the host through their interactions with intestinal microorganisms. Whether hormones in ruminal fluid have an association with the ruminal ecology is unknown. Objectives of the study were to examine relationships between the diurnal change in ruminal hormones and microbiota in lactating cows, and their associations in vivo and in vitro. For the in vivo study, six cows of similar weight (566.8 ± 19.6 kg), parity (3.0 ± 0.0), and milk performance (8,398.7 ± 1,392.9 kg/y) were used. They were adapted to natural light for 2 weeks before sampling and fed twice daily at 07:00 a.m. and 14:00 p.m. Serum, saliva, and ruminal fluid samples were collected at 02:00, 10:00, and 18:00 on the first day and 06:00, 14:00, and 22:00 on the second day of the experimental period. The concentrations of melatonin (MLT), growth hormone (GH), and prolactin (PRL) were measured via radioimmunoassay, whereas amplicon sequencing data were used to analyze relative abundance of microbiota in ruminal fluid. JTK_CYCLE analysis was performed to analyze circadian rhythms of hormone concentrations as well as the relative abundance of microbiota. For the in vitro study, exogenous MLT (9 ng) was added into ruminal fluid incubations to investigate the impacts of MLT on ruminal microbiota. The results not only showed that rumen fluid contains MLT, but the diurnal variation of MLT and the relative abundance of 9% of total rumen bacterial operational taxonomic units (OTUs) follow a circadian rhythm. Although GH and PRL were also detected in ruminal fluid, there was no obvious circadian rhythm in their concentrations. Ruminal MLT was closely associated with Muribaculaceae, Succinivibrionaceae, Veillonellaceae, and Prevotellaceae families in vivo. In vitro, these families were significantly influenced by melatonin treatment, as melatonin treatment increased the relative abundance of families Prevotellaceae, Muribaculaceae while it reduced the relative abundance of Succinivibrionaceae, Veillonellaceae. Collectively, ruminal microbes appear to maintain a circadian rhythm that is associated with the profiles of melatonin. As such, data suggest that secretion of melatonin into the rumen could play a role in host-microbe interactions in ruminants.

Dataset Information

Melatonin resynchronizes dysregulated circadian rhythm circuitry in human prostate cancer cells.

Publications

Melatonin resynchronizes dysregulated circadian rhythm circuitry in human prostate cancer cells.

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