Thioridazine enhances p62-mediated autophagy and apoptosis through Wnt/β-catenin signaling pathway in glioma cells

Cheng Wei Chu, Huey Jiun Ko, Chia Hua Chou, Tai Shan Cheng, Hui Wen Cheng, Yu Hsin Liang, Yun Ling Lai, Chen Yen Lin, Chihuei Wang, Joon Khim Loh, Jiin Tsuey Cheng, Shean Jaw Chiou, Chun Li Su, Chi Ying F. Huang, Yi Ren Hong

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10 Citations (Scopus)

Abstract

Thioridazine (THD) is a common phenothiazine antipsychotic drug reported to suppress growth in several types of cancer cells. We previously showed that THD acts as an antiglioblastoma and anticancer stem-like cell agent. However, the signaling pathway underlying autophagy and apoptosis induction remains unclear. THD treatment significantly induced autophagy with upregulated AMPK activity and engendered cell death with increased sub-G1 in glioblastoma multiform (GBM) cell lines. Notably, through whole gene expression screening with THD treatment, frizzled (Fzd) proteins, a family of G-protein-coupled receptors, were found, suggesting the participation of Wnt/β-catenin signaling. After THD treatment, Fzd-1 and GSK3β-S9 phosphorylation (inactivated form) was reduced to promote β-catenin degradation, which attenuated P62 inhibition. The autophagy marker LC3-II markedly increased when P62 was released from β-catenin inhibition. Additionally, the P62-dependent caspase-8 activation that induced P53-independent apoptosis was confirmed by inhibiting T-cell factor/β-catenin and autophagy flux. Moreover, treatment with THD combined with temozolomide (TMZ) engendered increased LC3-II expression and caspase-3 activity, indicating promising drug synergism. In conclusion, THD induces autophagy in GBM cells by not only upregulating AMPK activity, but also enhancing P62-mediated autophagy and apoptosis through Wnt/β-catenin signaling. Therefore, THD is a potential alternative therapeutic agent for drug repositioning in GBM.

Original languageEnglish
Article number473
JournalInternational journal of molecular sciences
Volume20
Issue number3
DOIs
Publication statusPublished - 2019 Feb 1

Keywords

  • Apoptosis
  • Autophagy
  • Glioblastoma
  • P62
  • Thioridazine
  • Wnt/β-catenin
  • Glioma/metabolism
  • Catenins/metabolism
  • Humans
  • Apoptosis/drug effects
  • Autophagy/drug effects
  • Cell Survival/drug effects
  • Wnt Signaling Pathway/drug effects
  • Cell Cycle/drug effects
  • Blotting, Western
  • Thioridazine/pharmacology
  • Receptors, G-Protein-Coupled/metabolism
  • Cell Line, Tumor
  • Beclin-1/metabolism

ASJC Scopus subject areas

  • Molecular Biology
  • Spectroscopy
  • Catalysis
  • Inorganic Chemistry
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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  • Cite this

    Chu, C. W., Ko, H. J., Chou, C. H., Cheng, T. S., Cheng, H. W., Liang, Y. H., Lai, Y. L., Lin, C. Y., Wang, C., Loh, J. K., Cheng, J. T., Chiou, S. J., Su, C. L., Huang, C. Y. F., & Hong, Y. R. (2019). Thioridazine enhances p62-mediated autophagy and apoptosis through Wnt/β-catenin signaling pathway in glioma cells. International journal of molecular sciences, 20(3), [473]. https://doi.org/10.3390/ijms20030473