title: CYLD Regulates Noscapine Activity in Acute Lymphoblastic Leukemia via a Microtubule-Dependent Mechanism.
abstract: Noscapine is an orally administrable drug used worldwide for cough suppression and has recently been demonstrated to disrupt microtubule dynamics and possess anticancer activity. However, the molecular mechanisms regulating noscapine activity remain poorly defined. Here we demonstrate that cylindromatosis (CYLD), a microtubule-associated tumor suppressor protein, modulates the activity of noscapine both in cell lines and in primary cells of acute lymphoblastic leukemia (ALL). Flow cytometry and immunofluorescence microscopy reveal that CYLD increases the ability of noscapine to induce mitotic arrest and apoptosis. Examination of cellular microtubules as well as in vitro assembled microtubules shows that CYLD enhances the effect of noscapine on microtubule polymerization. Microtubule cosedimentation and fluorescence titration assays further reveal that CYLD interacts with microtubule outer surface and promotes noscapine binding to microtubules. These findings thus demonstrate CYLD as a critical regulator of noscapine activity and have important implications for ALL treatment.
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Yunfan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ran
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.affiliation: 2. Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Sun
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Youguang
authors.initials: Y
authors.lastname: Luo
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.lastname: Tala
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Dengwen
authors.initials: D
authors.lastname: Li
authors.affiliation: 3. State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 2. Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Bao
authors.affiliation: 1. State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin 300071, China. ; 2. Department of Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
mesh_terms: D017209:Apoptosis; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D000074749:Deubiquitinating Enzyme CYLD; D006801:Humans; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008938:Mitosis; D009665:Noscapine / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D025521:Tumor Suppressor Proteins; D009665:Noscapine; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD
keywords: apoptosis.; leukemia; microtubule; mitotic arrest; noscapine