| Background Our previous study has found that ursolic acid (UA) increased intracellular reactive oxygen species (ROS) production and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation and cyclooxygenase-2 (COX-2) expression in gastric cancer cells. However, the molecular mechanism by which UA inhibits COX-2 expression in gastric cancer cells has not been fully clarified.Objective In this study we aimed to further clarify the signal transduction pathways involved in the UA-mediated inhibition of COX-2 expression in gastric cancer cells.Methods Human gastric cancer cell lines SGC-7901 and MKN-45 were routinely cultured in RPMI-1640(Roswell Park Memorial Institute-1640)medium supplemented with 10% heat-inactivated fetal calf serum. Sub-confluent cell cultures were pre-treated with antioxidant N-Acetyl-L-Cysteine(NAC), AMPK activator 5-amino-4-imida-zolecarboxamide-riboside(AICAR), AMPK inhibitor compound C, or STAT3 inhibitor WP1066 and then treated with or without UA for 24 h. The expression of AMPK and phosphorylated AMPK (p-AMPK), STAT3 and phosphorylated STAT3 (p-STAT3), as well as COX-2 was detected by Western blot analysis.Results Antioxidant NAC and AMPK inhibitor compound C blocked UA-induced inhibition of STAT3 phosphorylation and down-regulation of COX-2 expression in gastric cancer cells. Both AMPK activator AICAR and UA inhibited STAT3 phosphorylation and COX-2 expression; the combination of two drugs resulted in further reduction. STAT3 inhibitor WP1066 did not affect UA-induced AMPK phosphorylation, whereas inhibited STAT3 phosphorylation and COX-2 expression. The inhibitory effects on the STAT3 phosphorylation and COX-2 expression were significantly enhanced when SGC-7901 and MKN-45 cells were treated simultaneously with WP1066 plus UA..Conclusions UA inhibits COX-2 expression in gastric cancer cells may be mediated through ROS/AMPK/STAT3 signal transduction pathway. |
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