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

Research output: Contribution to journalArticle

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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

Fingerprint

Thioridazine
Catenins
Wnt Signaling Pathway
Autophagy
apoptosis
Cell death
Glioma
Apoptosis
drugs
cells
Glioblastoma
Cells
phenothiazines
proteins
Proteins
phosphorylation
Phosphorylation
AMP-Activated Protein Kinases
T-cells
stem cells

Keywords

  • Apoptosis
  • Autophagy
  • Glioblastoma
  • P62
  • Thioridazine
  • Wnt/β-catenin

ASJC Scopus subject areas

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

Cite this

Thioridazine enhances p62-mediated autophagy and apoptosis through Wnt/β-catenin signaling pathway in glioma cells. / Chu, Cheng Wei; Ko, Huey Jiun; Chou, Chia Hua; Cheng, Tai Shan; Cheng, Hui Wen; Liang, Yu Hsin; Lai, Yun Ling; Lin, Chen Yen; Wang, Chihuei; Loh, Joon Khim; Cheng, Jiin Tsuey; Chiou, Shean Jaw; Su, Chun-Li; Huang, Chi Ying F.; Hong, Yi Ren.

In: International journal of molecular sciences, Vol. 20, No. 3, 473, 01.02.2019.

Research output: Contribution to journalArticle

Chu, CW, Ko, HJ, Chou, CH, Cheng, TS, Cheng, HW, Liang, YH, Lai, YL, Lin, CY, Wang, C, Loh, JK, Cheng, JT, Chiou, SJ, Su, C-L, Huang, CYF & Hong, YR 2019, 'Thioridazine enhances p62-mediated autophagy and apoptosis through Wnt/β-catenin signaling pathway in glioma cells', International journal of molecular sciences, vol. 20, no. 3, 473. https://doi.org/10.3390/ijms20030473
Chu, Cheng Wei ; Ko, Huey Jiun ; Chou, Chia Hua ; Cheng, Tai Shan ; Cheng, Hui Wen ; Liang, Yu Hsin ; Lai, Yun Ling ; Lin, Chen Yen ; Wang, Chihuei ; Loh, Joon Khim ; Cheng, Jiin Tsuey ; Chiou, Shean Jaw ; Su, Chun-Li ; Huang, Chi Ying F. ; Hong, Yi Ren. / Thioridazine enhances p62-mediated autophagy and apoptosis through Wnt/β-catenin signaling pathway in glioma cells. In: International journal of molecular sciences. 2019 ; Vol. 20, No. 3.
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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.",
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AU - Chu, Cheng Wei

AU - Ko, Huey Jiun

AU - Chou, Chia Hua

AU - Cheng, Tai Shan

AU - Cheng, Hui Wen

AU - Liang, Yu Hsin

AU - Lai, Yun Ling

AU - Lin, Chen Yen

AU - Wang, Chihuei

AU - Loh, Joon Khim

AU - Cheng, Jiin Tsuey

AU - Chiou, Shean Jaw

AU - Su, Chun-Li

AU - Huang, Chi Ying F.

AU - Hong, Yi Ren

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N2 - 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.

AB - 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.

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