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

Chien Rui Lai, Yu Ling Tsai, Wen Chiuan Tsai, Tzu Min Chen, Hsin Han Chang, Chih Ying Changchien, Sheng Tang Wu, Hisao Hsien Wang, Ying Chen, Yu Huei Lin

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number4398
JournalCancers
Volume14
Issue number18
DOIs
Publication statusPublished - Sept 2022

Keywords

  • AMPK
  • angiogenesis
  • atorvastatin
  • bladder cancer
  • cholesterol
  • FXR
  • invasion
  • migration

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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