Melatonin is up‐regulator on small G‐protein mediated apoptotic cell death in cervical and endometrial cancer cells of human

Many gynecologic tumors are associated with infertility and spontaneous abortion that constitute a public problem. Recent studies have shown the main hormone of the pineal gland inhibit directly many different types of human tumor cells and naturally secreted cytotoxin, which induces tumor cell death(apoptosis). Additionally, activated Ras proteins have important roles on the regulation of apoptosis depending on cell type and other factors. Ras protein, a small GTP binding protein, send growth stimulating message to the nucleus through downstream small G protein such as Rac1 and Cdc42. Ras protein is an initiator of many tumors, and melatonin shows oncostatic action in various tumors cells. Whether melatonin can counteract the Ras‐involved functions remains unknown and is worth exploring. Thus, our overall hypothesis is that natural hormone melatonin regulates small GTP binding protein mediated apoptosis and we would demonstrate anti‐tumor function of melatonin in primary cultured human uterus cervix and endometrial cancer cells. What Ras gene transfected into cells were treated with melatonin, then observed increasing caspase‐3 expression suggesting turn of the apoptotic signal machinery. At physiological concentration of melatonin (1 nM), cell proliferation was decreased, suggesting cell cycle arrest through increasing p21 expression, which is mediated by p53(tumor suppressor gene). These observations indicate that melatonin, an endogenous hormone, inhibits the tumor cell proliferation suggesting melatonin should be developed as a therapeutic reagent. Supported by BioGreen21 Program (#20070401034006) of Rural Development Administration, South Korea