Farnesoid X Receptor Overexpression Decreases the Migration, Invasion and Angiogenesis of Human Bladder Cancers via AMPK Activation and Cholesterol Biosynthesis Inhibition.

Abstract

Simple SummaryOur previous studies characterized that FXR overexpression results in the inhibition of migratory, adhesive and angiogenic abilities through the proteosome degradation pathway in human bladder cancer cells. Since cholesterol metabolism plays an important role during cancer progression, we investigated the role of cholesterol biosynthesis-related proteins expression and their signal transduction pathway in human bladder cancer cells. We confirmed FXR overexpression decreased muscle invasive human bladder cancer cell T24’s metastatic ability in nude mice animal models. Moreover, statin usage showed potent enough efficacy to strengthen the enhancement of FXR-inhibited migration, adhesion and angiogenesis in human urothelial carcinoma cells. Additionally, clinical data showed survival benefits of statin usage in stage 0–I bladder cancer patients. Our results suggested that FXR overexpression, combined with atorvastatin treatment, may provide a potential therapeutic strategy for the treatment of human urothelial carcinoma in the future.Bladder cancer is one of the most prevailing cancers worldwide. Although treatments for urothelial carcinoma have improved, the rate of recurrence observed in the clinic is still high. The aim of this study was to evaluate whether cholesterol biosynthesis is involved in the effect of Farnesoid X Receptor (FXR) on bladder cancers. FXR overexpression contributed to activation of 5′ AMP-activated protein kinase (AMPK) and decreased cholesterol levels. FXR overexpression reduced cholesterol biosynthesis and secretion by downregulating Sterol Regulatory Element Binding Protein 2 (SREBP2) and 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR) expression. In addition, an AMPK inhibitor, dorsomorphin, reversed the inhibition of migration, invasion and angiogenesis by FXR overexpression. In a metastatic xenograft animal study, FXR overexpression suppressed bladder cancer lung metastasis by decreasing matrix metalloproteinase-2 (MMP2), SREBP2 and HMGCR expression. Moreover, FXR overexpression combined with atorvastatin treatment further enhanced the downregulation of the migratory, adhesive, invasive and angiogenic properties in human urothelial carcinoma. In clinical observations, statin administration was associated with better survival rates of early-stage bladder cancer patients. Our results may provide guidance for improving therapeutic strategies for the treatment of urothelial carcinoma.