u-0126 and 4-iodo-2-5-dimethoxyphenylisopropylamine

Serotonin 5-HT(2A) receptor activation improves viability, increases DNA synthesis and activates JAK2-STAT3 and MEK1/2-ERK1/2 signalling pathways in JEG-3 human trophoblast choriocarcinoma cells. The goal of this study was to characterize the signal transduction cascade involved in 5-HT(2A) receptor-induced growth of JEG-3 cells. Selective 5-HT(2A) receptor agonist, DOI, induced JEG-3 cell growth was inhibited by the inhibitor of JAK2 (AG490), MEK1/2 (U0126), phospholipase C-β (PLC-β; U73122) and protein kinase C-β (PKC-β; Gö6976)), whereas the selective phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002) had no effect. Specific inhibitors of PLC-β, PKC-β and Ras (farnesylthiosalicylic acid) inhibit activation of ERK1/2, whereas the PKC-ζ inhibitor GF109203X had no effect. Interestingly, inhibition of JAK2 prevented DOI-induced phosphorylation of ERK1/2 whereas inhibition of ERK1/2 pathway had no effect on DOI-induced activation of STAT3. Taken together, our results demonstrate that both the JAK2-STAT3 and PLC-β-PKC-β-Ras-ERK1/2 signalling pathways are involved in the stimulation of JEG-3 cell growth mediated by DOI. Moreover, this study shows that activation of JAK2 by the 5-HT(2A) receptor is essential to activate both STAT3 and ERK1/2 signalling pathways as well as to increase JEG-3 choriocarcinoma cell growth and survival.

Topics: Amphetamines; Butadienes; Carbazoles; Cell Line, Tumor; Cell Proliferation; Cell Survival; Choriocarcinoma; Estrenes; Female; Humans; Janus Kinase 2; MAP Kinase Signaling System; Nitriles; Phosphatidylinositol 3-Kinase; Phospholipase C beta; Phosphorylation; Pregnancy; Protein Kinase C; Protein Kinase C beta; Pyrrolidinones; Receptor, Serotonin, 5-HT2A; Signal Transduction; STAT3 Transcription Factor; Tyrphostins