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Related Experiment Video

Updated: Jun 27, 2025

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GW501516-Mediated Targeting of Tetraspanin 15 Regulates ADAM10-Dependent N-Cadherin Cleavage in Invasive Bladder

Alexandre Barbaud1, Isabelle Lascombe1, Adeline Péchery1

  • 1SINERGIES-LabEx LipSTIC ANR-11-LABX-0021, Université de Franche-Comté, F-25000 Besançon, France.

Cells
|April 26, 2024
PubMed
Summary

GW501516, a PPARβ/δ agonist, reduces Tspan15, preventing N-cadherin cleavage and pro-tumoral fragment release in bladder cancer. This offers a potential therapeutic strategy by inhibiting tumor progression and metastasis.

Keywords:
ADAM10GW501516N-cadherinPPARβ/δbladder cancertetraspanin 15

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Area of Science:

  • Molecular oncology
  • Cancer cell biology

Background:

  • Bladder cancer aggressiveness correlates with abnormal N-cadherin expression.
  • N-cadherin is cleaved by ADAM10 and γ-secretase, releasing pro-angiogenic (NTF) and proliferation-activating (CTF2) fragments.
  • Tetraspanin 15 (Tspan15) interacts with ADAM10 to selectively cleave N-cadherin.

Purpose of the Study:

  • To investigate the role of Tspan15 in N-cadherin cleavage in bladder cancer.
  • To evaluate the effect of GW501516 on N-cadherin cleavage and its fragments.
  • To explore GW501516 as a potential therapeutic agent for bladder cancer.

Main Methods:

  • Demonstration of N-cadherin cleavage by ADAM10 in T24 bladder cancer cells.
  • Assessment of Tspan15's requirement for ADAM10-mediated N-cadherin cleavage.
  • Treatment of cells with GW501516 and analysis of Tspan15 levels and N-cadherin cleavage products.

Main Results:

  • Tspan15 is essential for ADAM10 to cleave N-cadherin, generating extracellular NTF and membrane-anchored CTF1.
  • GW501516, a PPARβ/δ agonist, decreased Tspan15 expression.
  • GW501516 effectively prevented N-cadherin cleavage, reducing NTF levels without altering ADAM10 expression.

Conclusions:

  • Tspan15 mediates ADAM10-dependent N-cadherin cleavage in bladder cancer cells.
  • GW501516 inhibits N-cadherin cleavage by targeting Tspan15, reducing pro-tumoral NTF.
  • GW501516 represents a promising therapeutic strategy for bladder cancer, potentially enhancing N-cadherin antagonist efficacy.