Melatonin modulates proliferation of pancreatic stellate cells through caspase-3 activation and changes in cyclin A and D expression

• Published in: Journal of physiology and biochemistry 2020-05, Vol.76 (2), p.345-355
• Main Authors: Estaras, Matias, Peña, Fernando J., Tapia, José A., Fernandez-Bermejo, Miguel, Mateos, Jose M., Vara, Daniel, Roncero, Vicente, Blanco, Gerardo, Lopez, Diego, Salido, Gines M., Gonzalez, Antonio
• Format: Article
• Language: English
• Subjects: Animal Physiology; Animals; Apoptosis; Biomedical and Life Sciences; Biomedicine; Calcium-binding protein; Calmodulin; Caspase 3 - metabolism; Caspase-3; Cell activation; Cell cycle; Cell proliferation; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell viability; Cells, Cultured; Cyclin A; Cyclin A - metabolism; Cyclin D; Cyclin D - metabolism; Fibrosis; Human Physiology; Melatonin; Melatonin - pharmacology; Melatonin receptors; Original Article; Pancreas; Pancreatic diseases; Pancreatic Stellate Cells - cytology; Pancreatic Stellate Cells - drug effects; Rats; Rats, Wistar; Regulators; Stellate cells; Time dependence
• ISSN: 1138-7548; 1877-8755
• DOI: 10.1007/s13105-020-00740-6

In this study, the effects of melatonin (1 μM–1 mM) on pancreatic stellate cells (PSC) have been examined. Cell viability and proliferation, caspase-3 activation, and the expression of cyclin A and cyclin D were analyzed. Our results show that melatonin decreased PSC viability in a time- and concentration-dependent manner. This effect was not inhibited by treatment of cells with MT1, MT2, calmodulin, or ROR-alpha inhibitors prior to melatonin addition. Activation of caspase-3 in response to melatonin was detected. The expression of cyclin A and cyclin D was decreased in cells treated with melatonin. Finally, changes in BrdU incorporation into the newly synthesized DNA of proliferating cells were also observed in the presence of melatonin. We conclude that melatonin, at pharmacological concentrations, modulates proliferation of PSC through activation of apoptosis and involving crucial regulators of the cell cycle. These actions might not require specific melatonin receptors. Our observations suggest that melatonin, at high doses, could potentially exert anti-fibrotic effects and, thus, could be taken into consideration as supportive treatment in the therapy of pancreatic diseases.