Antiproliferative activity of melatonin by transcriptional inhibition of cyclin D1 expression: a molecular basis for melatonin-induced oncostatic effects
Article first published online: 25 JAN 2005
Journal of Pineal Research
Volume 39, Issue 1, pages 12–20, August 2005
How to Cite
Cini, G., Neri, B., Pacini, A., Cesati, V., Sassoli, C., Quattrone, S., D'Apolito, M., Fazio, A., Scapagnini, G., Provenzani, A. and Quattrone, A. (2005), Antiproliferative activity of melatonin by transcriptional inhibition of cyclin D1 expression: a molecular basis for melatonin-induced oncostatic effects. Journal of Pineal Research, 39: 12–20. doi: 10.1111/j.1600-079X.2004.00206.x
- Issue published online: 25 JAN 2005
- Article first published online: 25 JAN 2005
- Received August 5, 2004; accepted November 3, 2004.
- cAMP responsive element;
- cell cycle;
- cyclin D1;
- MCF-7 cells;
Abstract: Melatonin is endowed with a growth inhibitory effect in MCF-7 breast cancer cells whose mechanism has been related to an antiestrogenic activity exerted by inhibition of binding of the estradiol–estrogen receptor complex to its DNA responsive element. Looking for downstream gene determinants of this effect, we performed a transcriptome profiling by high-density microarrays of estrogen-treated MCF-7 cells exposed or not to melatonin. We found that cyclin D1 was one of the main downregulated genes by melatonin. Validation experiments clearly confirm that in MCF-7 cells the estrogen-induced growth inhibitory activity of melatonin is consistently associated with inhibition of estrogen-elicited cyclin D1 induction. This effect is almost purely transcriptional. Reporter gene assays indicate that the same portion of the cyclin D1 promoter which confers estrogen sensitivity, encompassing a potential cAMP responsive element binding site, is repressed by melatonin. Transcriptional downregulation of cyclin D1 is the key molecular event for melatonin's antiproliferative activity, as this activity can be completely and selectively rescued by transient cyclin D1 overexpression. Finally, we provide indirect evidence that the effect of melatonin on the cyclin D1 promoter is mediated by the c-jun and ATF-2 proteins, known to bind the minimal estrogen-sensitive cyclin D1 promoter element. These findings establish for the first time a molecular link between melatonin and its effects on the cell cycle, providing at the same time a rationale for its use in adjuvant chemotherapy.