Melatonin resynchronizes dysregulated circadian rhythm circuitry in human prostate cancer cells.
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.
Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA.
Brittney
B
Jung-Hynes
Wei
W
Huang
Russel J
RJ
Reiter
Nihal
N
Ahmad
D056930:ARNTL Transcription Factors / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D056926:CLOCK Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002940:Circadian Rhythm / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000378:metabolism
D056930:ARNTL Transcription Factors; C538960:BMAL1 protein, human; C063898:DBP protein, human; D004268:DNA-Binding Proteins; C421902:PER2 protein, human; D056950:Period Circadian Proteins; D014157:Transcription Factors; D056926:CLOCK Proteins; C538943:CLOCK protein, human; D011065:Poly(ADP-ribose) Polymerases; D008550:Melatonin