fh535 and Neoplasm-Metastasis

Surgery is the major treatment method for non-small cell lung cancer. It has been reported that plasma PGE2 level is increased following surgery and stress which promotes lung cancer metastasis. In the present study, two animal models were used to confirm the effects of exogenous and endogenous prostaglandin E2 (PGE2) on metastasis of lung cancer cells. We found that both PGE2 level and A549 metastasis were enhanced in mice with unilateral pulmonary resection following tail vein injection of lung cancer A549 cells. Both endogenous PGE2 level and pulmonary metastatic nodules were significantly reduced by celecoxib. A549 metastases were increased in mice after exogenous PGE2 injection. In the animal models, celecoxib inhibited lung cancer cell metastasis induced by exogenous PGE2. Therefore, we focused on the effects of celecoxib on the downstream pathway of PGE2 in vitro and found that celecoxib inhibited PGE2-induced A549 migration and invasion, which were evaluated by wound healing and Transwell experiments. The expression of protein and mRNA of MMP9 and E-cadherin following treatment with PGE2 were suppressed and increased by celecoxib, respectively; however, MMP2 showed no change. A549 cell invasion and up-regulation of the expression of MMP9 and down-regulation of E-cadherin induced by PGE2 were inhibited by FH535, an inhibitor of β-catenin. Deletion of β-catenin by siRNA abrogated celecoxib-induced inhibition of MMP9 up-regulation and E-cadherin down-regulation by treatment of PGE2. Furthermore, we found that the level of β-catenin together with GSK-3β phosphorylation was inhibited by celecoxib. In conclusion, celecoxib inhibits metastasis of A549 cells in the circulation enhanced by PGE2 after surgery by not only inhibiting endogenous PGE2 expression, but also by suppression downstream of PGE2 via the GSK-3β-β-catenin pathway.

Topics: Animals; Antigens, CD; beta Catenin; Cadherins; Celecoxib; Cell Line, Tumor; Cell Proliferation; Dinoprostone; Down-Regulation; Female; Gene Deletion; Gene Expression Regulation, Neoplastic; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Lung Neoplasms; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Phosphorylation; Pyrazoles; RNA, Messenger; RNA, Small Interfering; Sulfonamides; Up-Regulation