Signal transduction pathway of ursolic acid inhibiting COX-2 expression in gastric cancer cells / 中国药理学通报

ABSTRACT

Aim Our previous study has found that ur-solic acid( UA) increased intracellular reactive oxygen species ( ROS ) production and adenosine monophos-phate-activated protein kinase ( AMPK ) phosphoryla-tion, inhibited signal transducer and activator of tran-scription 3 ( STAT3 ) phosphorylation and cyclooxygen-ase-2 ( COX-2 ) expression in gastric cancer cells . However , the molecular mechanism by which UA in-hibits COX-2 expression in gastric cancer cells has not been fully clarified .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 medium supplemented with 10% heat-in-activated fetal calf serum .Sub-confluent cell cultures were pre-treated with antioxidant N-acetylcysteine ( NAC) , AMPK activator 5-amino-4-imida-zolecarbox-amide-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 phos-phorylated STAT3 ( p-STAT3 ) , as well as COX-2 was detected by Western blot analysis .Results Antioxi-dant NAC and AMPK inhibitor compound C blocked UA-induced inhibition of STAT 3 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 it inhibited STAT3 phosphorylation and COX-2 expression .The inhibitory effects on the STAT3 phosphorylation and COX-2 ex-pression were significantly enhanced when SGC-7901 and MKN-45 cells were treated simultaneously with WP1066 plus UA.Conclusion UA inhibits COX-2 expression in gastric cancer cells , which may be medi-ated through ROS/AMPK/STAT3 signal transduction pathway .