{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T20:22:07Z","timestamp":1789590127282,"version":"build-2803163510"},"reference-count":39,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2019,1,22]],"date-time":"2019-01-22T00:00:00Z","timestamp":1548115200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\/\u03b2-catenin signaling. After THD treatment, Fzd-1 and GSK3\u03b2-S9 phosphorylation (inactivated form) was reduced to promote \u03b2-catenin degradation, which attenuated P62 inhibition. The autophagy marker LC3-II markedly increased when P62 was released from \u03b2-catenin inhibition. Additionally, the P62-dependent caspase-8 activation that induced P53-independent apoptosis was confirmed by inhibiting T-cell factor\/\u03b2-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\/\u03b2-catenin signaling. Therefore, THD is a potential alternative therapeutic agent for drug repositioning in GBM.<\/jats:p>","DOI":"10.3390\/ijms20030473","type":"journal-article","created":{"date-parts":[[2019,1,24]],"date-time":"2019-01-24T03:52:32Z","timestamp":1548301952000},"page":"473","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":118,"title":["Thioridazine Enhances P62-Mediated Autophagy and Apoptosis Through Wnt\/\u03b2-Catenin Signaling Pathway in Glioma Cells"],"prefix":"10.3390","volume":"20","author":[{"given":"Cheng-Wei","family":"Chu","sequence":"first","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Division of Neurosurgery, Department of Surgery, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huey-Jiun","family":"Ko","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Hua","family":"Chou","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai-Shan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Laboratory Science in Medicine, Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Wen","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Laboratory Science in Medicine, Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Hsin","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Laboratory Science in Medicine, Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Ling","family":"Lai","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Yen","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihuei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joon-Khim","family":"Loh","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan"},{"name":"Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiin-Tsuey","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shean-Jaw","family":"Chiou","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan"},{"name":"Department of Biochemistry &amp; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Li","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Ying F.","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Laboratory Science in Medicine, Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan"},{"name":"Department of Biochemistry &amp; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ren","family":"Hong","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan"},{"name":"Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan"},{"name":"Department of Biochemistry &amp; 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