Antitumoral effect of melatonin by G‐protein mediated toll‐like receptor (TLR) activation through autophagic cell death in gynecologic cancer cells

Toll‐like receptors(TLRs) induce innate immune responses that are essential for host defenses against invading microbial pathogens. Toll‐like receptor 4(TLR‐4) mediates many biological effects of lipopolysaccharide(LPS), which has antitumoral effects on tumor cells. However, the cellular mechanism of these antitumoral effects remains unknown. Here, we speculated that stimulation of TLR‐4 signaling by G‐protein activation plays important roles, which gives signal to stimulate of autophagic cell death in genecologic tumor, not to lead the activation of NF‐kB and inflammatory pathway. The role of TLR‐4 in the antitumoral effect of LPS was assessed in primary cultured cervical, endometrial and angioma cells. Cancer cells were transiently transfected with small G‐protein encoding plasmids, and then treated with LPS. Immunofluorescence microscopy, western blotting, and RT‐PCR were performed. LPS activated TLR‐4 and caused activation of autophagosome formation. However, when cells transfected with G‐protein, we observed inhibition of inflammatory cytokines pathway. These effects were induced by overexpression of G‐protein and lead cell death pathway such as apoptosis. These studies suggest that activation of G‐protein mediated TLR‐4 signaling induces autophagic cell death, not to lead necrotic cell death. Supported by KRF‐E00344, BioGreen21 Program (#20070401034006) of Rural Development Administration, South Korea.