Melatonin-induced inhibition of proliferation and G(1)/S cell cycle transition delay of human choriocarcinoma JAr cells: Possible involvement of MT2 (MEL1B) receptor

Melatonin, the pineal neurohormone, is an evolutionarily conserved photoper iodic signaling molecule with diverse functions that include the entrainmen t of human circadian rhythms. Although evidence supporting a direct inhibit ory action of melatonin on human cancer cell proliferation exists in the li terature, the molecular and cellular signaling mechanisms involved are larg ely undefined. In our study, significant inhibition of human choriocarcinom a JAr cell proliferation at physiological and pharmacological concentration s of melatonin was observed. 2-Iodomelatonin, a high affinity melatonin rec eptor agonist, was more potent than melatonin in inhibiting JAr cell prolif eration. In addition, the presence of putative melatonin receptors in chori ocarcinoma was suggested by the demonstration of specific 2-[I-125]iodomela tonin binding to the tumor. Interestingly, the selective MT, melatonin rece ptor ligand, 4-phenyl-3-propionamidotetraline (4-P-PDOT), was found to exer t not only concentration-dependent anti-proliferative actions on JAr cells, but also additive effects with melatonin in inhibiting JAr cell proliferat ion. Furthermore, MT2 melatonin receptor gene expression by JAr cells was d emonstrated by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization (ISH). Taken together: our data suggest that the rep orted anti-proliferative action of melatonin on human choriocarcinoma JAr c ells may be mediated, in part, by MT, melatonin receptor. Moreover. analysi s of melatonin effect on cell cycle kinetics indicated that G(1)/S transiti on delay map underlie the observed inhibition of choriocarcinoma cell proli feration by melatonin.