Alpha-estradiol and (R)-(-)-ibuprofen inhibit gastric cancer progression via GLI1 G-quadruplex

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Gastric cancer progression is driven by aberrant GLI1 activation, a target lacking approved inhibitors.
• G-quadruplex (G4) motifs in gene promoter regions represent emerging therapeutic targets.
• This study investigates G4 stabilization in the GLI1 promoter as a novel anti-gastric cancer strategy.

Purpose of the Study:

• To explore G-quadruplex stabilization in the GLI1 promoter as a novel strategy to suppress gastric cancer progression.
• To identify FDA-approved drugs capable of stabilizing G4 structures in the GLI1 promoter.
• To evaluate the anti-tumor efficacy and underlying mechanisms of identified G4 stabilizers.

Main Methods:

• Validated G-quadruplex formation in the GLI1 promoter using circular dichroism.
• Screened FDA-approved drugs for G4-stabilizing activity via dual-luciferase assays, identifying alpha-estradiol and (R)-(-)-ibuprofen.
• Assessed anti-tumor effects in vitro and in vivo, and elucidated mechanisms via chromatin immunoprecipitation and pathway analysis.

Main Results:

• Confirmed stable G-quadruplex structures in the GLI1 promoter.
• Alpha-estradiol and (R)-(-)-ibuprofen suppressed GLI1 transcription and protein, inhibiting gastric cancer cell proliferation, migration, invasion, and stemness.
• In vivo studies showed reduced tumor growth and metastasis; (R)-(-)-ibuprofen synergized with cisplatin. Mechanistically, G4 stabilization downregulated PRKACB, impairing epithelial-mesenchymal transition and cancer stemness.

Conclusions:

• Targeting GLI1 G4 structures with alpha-estradiol and (R)-(-)-ibuprofen inhibits gastric cancer progression by blocking GLI1/PRKACB signaling.
• This G4-targeted therapy demonstrates potential as a novel and clinically translatable strategy for gastric cancer treatment.