title: Clioquinol induces pro-death autophagy in leukemia and myeloma cells by disrupting the mTOR signaling pathway.
abstract: Clioquinol is an anti-microbial drug, and it was recently found to induce cancer cell death. In the present study, clioquinol was found to trigger autophagy by inducing LC3 lipidation and autophagosome formation which was abolished by an autophagy inhibitor 3-methyladenine. Further study showed clioquinol displayed no effects on PI3KC3 or Beclin 1 expression but downregulated the expression and the enzymatic activity of mammalian target of Rapamycin (mTOR), a critical modulator of autophagy. Moreover, clioquinol inhibited the catalytic activity of the mTOR complex 1, thus suppressing phosphorylation of P70S6K and 4E-BP1, two major proteins associated with autophagy in the mTORC1 signaling pathway. Clioquinol induced leukemia and myeloma cell apoptosis, however, addition of autophagy inhibitor 3-methyladenine attenuated this kind of cell death. Therefore, this study demonstrated that clioquinol induces autophagy in associated with apoptosis in leukemia and myeloma cells by disrupting mTOR signaling pathway.
authors.affiliation: 1] Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho- diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China [2] Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, China [3].
authors.forename: Biyin
authors.initials: B
authors.lastname: Cao
authors.affiliation: 1] Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho- diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China [2] Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, China [3].
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215106, China.
authors.forename: Xiumin
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho- diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.
authors.forename: Jiaxiang
authors.initials: J
authors.lastname: Juan
authors.affiliation: 1] Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho- diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China [2] Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, China.
authors.forename: Kunkun
authors.initials: K
authors.lastname: Han
authors.affiliation: 1] Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho- diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China [2] Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, China.
authors.forename: Zubin
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, 215106, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, China.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1] Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-psycho- diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China [2] Cyrus Tang Hematology Center, Soochow University, Suzhou, 215123, China [3] Collaborative Innovation Center of Hematology, Soochow University, China.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Mao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071186:Beclin-1; D045744:Cell Line, Tumor; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism; D007464:Clioquinol / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D007464:Clioquinol; C546842:MTOR protein, human; D058544:Class Ib Phosphatidylinositol 3-Kinase; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases