Benign and Tumor Prostate Cells as Melatonin Target Sites

Abstract

Melatonin, secreted nocturnally by the pineal gland into the circulation, affects behavioral and physiological adaptation of the organism to the light and dark cycles. To date, the physiological study of melatonin’s role has focused primarily on the pituitary-gonadal axis, and there is little information on the direct effects of melatonin on peripheral organs. The prostate gland is apparently a peripheral target for melatonin. Recent data indicate that human benign and tumor prostate epithelial cells express functional melatonin receptors. At physiological concentrations, melatonin is able to suppress DNA synthesis transiently and inhibit cyclic guanosine monophosphate (cGMP) in the benign prostate epithelial cells. These effects are mediated via heterotrimeric guanosine triphosphate (GTP)-binding proteins and involve TGFβ1. The transient nature of melatonin responses in the prostate cells reflects inactivation of the receptors via a protein kinase C (PKC)-mediated pathway. Recent data demonstrate differential interaction of melatonin with androgen receptor-negative and -positive prostate cells. In the androgen-sensitive LNCaP cells, melatonin attenuates cell growth. As in the benign epithelial cells, this attenuation is transient, probably due to inactivation of the receptors via a PKC-mediated pathway. The androgen insensitive PC3 cells express low affinity melatonin binding sites. Unlike the benign cells, melatonin receptors in the PC3 cells are coupled to pertussis toxin (PTX)-sensitive G proteins to induce cell density-dependent changes in cGMP, cyclic adenosine monophosphate (cAMP) and cell growth. The data imply that androgen receptors play a crucial role in the melatonin-mediated regulation of prostate cell growth. The possibility that melatonin may impinge on androgen-dependent pathways in the prostate is extremely intriguing, since it may lead to the development of new strategies to manipulate benign and tumor prostate growth.