2. Academic Validation
  3. GW4064 inhibits migration and invasion through cathepsin B and MMP2 downregulation in human bladder cancer

GW4064 inhibits migration and invasion through cathepsin B and MMP2 downregulation in human bladder cancer

  • Chem Biol Interact. 2024 Jan 10:389:110869. doi: 10.1016/j.cbi.2024.110869.
Chien-Chang Kao 1,  Chien-Rui Lai 2,  Yi-Hsuan Lin 2,  Tzu-Min Chen 2,  Yu-Ling Tsai 3,  Wen-Chiuan Tsai 3,  Tze-Yun Ong 4,  Hisao-Hsien Wang 5,  Sheng-Tang Wu 6,  Ying Chen 7
Affiliations

Affiliations

  • 1 Division of Urology, Department of Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan.
  • 2 Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan.
  • 3 Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
  • 4 Department of Medicine, National Defense Medical Center, Taipei, Taiwan.
  • 5 Department of Urology, Cheng Hsin General Hospital, Taipei, Taiwan.
  • 6 Division of Urology, Department of Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan; Division of Urology, Department of Surgery, Hualien Armed Forces General Hospital, Hualien, Taiwan. Electronic address: doc20283@mail.ndmctsgh.edu.tw.
  • 7 Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan. Electronic address: ychen0523@mail.ndmctsgh.edu.tw.
PMID: 38216027 DOI: 10.1016/j.cbi.2024.110869
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 β3 expression and Myosin light chain phosphorylation were decreased after GW4064 treatment. Immunocytochemistry showed an increase in E-cadherin and a decrease in β-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 β-catenin. Moreover, GW4064 reduced the invasion of muscle-invasive T24 cells. The GW4064-decreased migration and invasion were reversed by the Proteasome Inhibitor MG132 and the lysosome inhibitor NH4Cl. Furthermore, the GW4064-induced inhibition of matrix metalloproteinase-2 (MMP2) and Cathepsin B expression was reversed by NH4Cl. Xenograft animal studies revealed that GW4064 declined MMP2, Cathepsin B and lung metastasis of bladder Cancer. 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.

Keywords

Bladder cancer; GW4064; Invasion; Lysosomal degradation; Migration; Proteasomal degradation.

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