Thioridazine Enhances P62-Mediated Autophagy and Apoptosis Through Wnt/β-Catenin Signaling Pathway in Glioma Cells

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Thioridazine (THD), a phenothiazine antipsychotic, exhibits anticancer properties, particularly against glioblastoma.
• Previous studies identified THD as an antiglioblastoma and anticancer stem-like cell agent.
• The precise molecular mechanisms driving THD-induced autophagy and apoptosis in glioblastoma multiforme (GBM) remain incompletely understood.

Purpose of the Study:

• To elucidate the signaling pathways involved in THD-induced autophagy and apoptosis in GBM.
• To investigate the role of Wnt/β-catenin signaling in THD's anticancer effects.
• To evaluate the potential synergistic effect of THD combined with temozolomide (TMZ) in GBM treatment.

Main Methods:

• Whole gene expression screening to identify signaling pathways affected by THD.
• Analysis of key proteins involved in autophagy (AMPK, LC3-II, P62) and Wnt/β-catenin signaling (Fzd-1, GSK3β, β-catenin).
• Assessment of apoptosis markers (sub-G1, caspase-8, caspase-3) and autophagy flux inhibition.

Main Results:

• THD treatment significantly upregulated AMPK activity and induced autophagy in GBM cell lines.
• THD modulated Wnt/β-catenin signaling by reducing Fzd-1 and GSK3β phosphorylation, leading to β-catenin degradation and P62 release.
• P62-mediated autophagy and apoptosis were confirmed, with increased LC3-II and caspase-8 activation. Combined THD and TMZ treatment showed synergistic effects.

Conclusions:

• THD induces autophagy and apoptosis in GBM cells through AMPK activation and Wnt/β-catenin pathway modulation, enhancing P62-mediated effects.
• THD demonstrates potential as a therapeutic agent for glioblastoma multiforme through drug repositioning.
• The combination of THD and TMZ exhibits promising synergistic anticancer activity in GBM.