Verteporfin blocks Clusterin which is required for survival of gastric cancer stem cell by modulating HSP90 function

Area of Science:

• Oncology
• Molecular Biology
• Cancer Stem Cell Research

Background:

• Gastric cancer stem cells (GCSCs) drive tumor recurrence, metastasis, and drug resistance.
• The molecular mechanisms governing GCSC survival and potential therapeutic targets remain largely unknown.

Purpose of the Study:

• To identify key molecules involved in GCSC survival.
• To discover drugs targeting GCSC survival pathways.

Main Methods:

• Mass spectrometry to identify proteins in sphere-forming GCSCs.
• Analysis of clusterin expression in primary gastric cancer (GC) tissues.
• Clusterin depletion experiments (silencing).
• Drug screening to identify GCSC-targeting agents.
• GCSC xenograft models in mice.

Main Results:

• Increased secreted clusterin (S-Clu) expression was detected in GCSC spheres.
• Clusterin overexpression (77% of cases) correlated with advanced T stage, lymph node metastasis, and TNM stage.
• Clusterin depletion induced GCSC apoptosis and tumorsphere declustering.
• Clusterin interacts with heat shock protein 90 beta (HSP90) to regulate client protein levels.
• Verteporfin (VP) inhibited clusterin expression, reduced HSP90 client proteins, and selectively killed GCSCs.
• Both clusterin silencing and VP treatment suppressed tumor growth in GCSC xenografts.

Conclusions:

• Clusterin is a critical regulator of GCSC survival and progression.
• Verteporfin demonstrates potent GCSC-eradicating effects.
• Targeting clusterin and/or using VP offers a promising therapeutic strategy for gastric cancer, potentially reducing mortality.