使用Farnesoid X receptor 抑制劑GW4064藉由降解β-catenin及MMP2抑制人類膀胱腫瘤的爬行及侵入能力

高建璋¹、吳勝堂¹、查岱龍¹、陳瀅²

三軍總醫院 外科部 泌尿科¹；國防醫學院 生物及解剖學²

The farnesoid X receptor agonist GW4064 inhibits migration and invasion through β-catenin and MMP2 downregulation in human bladder cancer

Chien-Chang Kao¹, Sheng-Tang Wu¹, Dai-Lung Cha¹, Ying Chen²  

1. Divisions of Urology, Department of Surgery, Tri-service general hospital, National Defense Medical Center, Taipei 11490, Taiwan
2. Department of Biology and Anatomy, National Defense Medical Center, Taipei 11490, Taiwan

Abstract

The ability of bladder cancer to invade and metastasize often leads to poor prognosis in bladder cancer patients. The aim of this study was to evaluate the effect of the farnesoid X receptor (FXR) agonist GW4064 on the migration and invasion of human bladder cancer cells. Long-term exposure to GW4064 decreased the colony formation of RT4 and T24 cells. The wound healing migration assay revealed an inhibitory effect of GW4064 on both of these bladder cancer cell lines. In addition, integrin b3 expression and myosin light chain phosphorylation were decreased after GW4064 treatment. Immunocytochemistry showed an increase in E-cadherin and a decrease in b-catenin in the cell membrane of bladder cancer cells. Total protein expression and membrane fractionation assays also indicated upregulation of E-cadherin and downregulation of b-catenin. Moreover, GW4064 reduced the invasion of muscle-invasive T24 cells. The GW4064-induced decreases in migration and invasion were reversed by the proteasome inhibitor MG132 and the lysosome inhibitor NH4Cl, respectively. Furthermore, the GW4064-induced inhibition of matrix metalloproteinase-2 (MMP2) and cathepsin B expression was reversed by NH4Cl. In conclusion, GW4064 decreases the migration and invasion of human bladder cancer cells, which may provide a new therapeutic strategy for the treatment of human bladder cancer.