AMPK/ULK1 and JNK/p38/ERK Regulate Serotonin (5‐hydroxytryptamine) -induced Autophagy in Hepatoma Cells

Abstract It has been reported that serotonin (5-hydroxytryptamine, 5‐HT), autophagy and ROS are involved in the pathogenesis of cancer, here, we used HepG2 and Hep3B cells as model cells to investigate whether 5-HT could induce hepatoma cells autophagy and its possible mechanisms involved in ROS. First, the immunofluorescence results showed that 5-HT could induce the production of LC3 in hepatoma cells, and western blot results showed that 5-HT induced a complete autophagy process in hepatoma cells. Secondly, our results showed that 5-HT induced autophagy through the AMPK/ULK1 instead of the mTOR-dependent pathway in hepatoma cells. Thirdly, 5-HT also could stimulate autophagy through JNK/p38/ERK pathway activation in hepatoma cells. Finally, the DHR 123 assay showed that 5-HT could induce ROS production in hepatoma cells and the ROS scavenger NAC significantly inhibited the 5-HT-induced LC3 in hepatoma cells, this showed that ROS was necessary for 5-HT-induced autophagy in hepatoma cells. Therefore, we demonstrated that 5-HT induced autophagy in hepatoma cells, which was mediated by respective AMPK/ULK1 and JNK/p38/ERK pathways not by inhibiting phosphorylation of the mTOR pathway, and ROS participated in the occurrence of 5-HT-induced autophagy. This provided a theoretical basis for the important effects of 5-HT in the treatment or prevention of cancer, and provided new ideas for the development of new anti-cancer drugs targeting 5-HT receptors.