CYLD Regulates Noscapine Activity in Acute Lymphoblastic Leukemia via a Microtubule-Dependent Mechanism

• Type of Material: Article
• Authors: Yunfan Yang, Nankai University; Jie Ran, Nankai University; Lei Sun, Nankai University; Xiaodong Sun, Emory University; Youguang Luo, Nankai University; Bing Yan, Nankai University; Min Liu, Nankai University; Dengwen Li, Nankai University; Lei Zhang, Chinese Academy of Sciences; Gang Bao, Emory University; Jun Zhou, Emory University
• Language: English
• Date: 2015-01-01
• Publisher: IVYSPRING INT PUBL
• Publication Version: Final Published Version
• Copyright Statement: © 2015 Ivyspring International Publisher. CC BY NC 4.0
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.7150/thno.10844
• Title of Journal or Parent Work: Theranostics
• Volume: 5
• Issue: 7
• Start Page: 656
• End Page: 666
• Grant/Funding Information: This work was supported by grants from the National Basic Research Program of China (2012CB945002 to J; the National Natural Science Foundation of China (31130015, 31471262, and 91313302 to JZ); and the US National Science Foundation (CBET-0939511 to GB).
• Keywords: BREAST-CANCER; leukemia; noscapine; APOPTOSIS; Research & Experimental Medicine; apoptosis; microtubule; AGENT; TUMOR-SUPPRESSOR CYLD; DYNAMICS; Medicine, Research & Experimental; Science & Technology; Life Sciences & Biomedicine; MITOSIS; mitotic arrest; PACLITAXEL SENSITIVITY; GENE
• Research Categories: Health Sciences, Medicine and Surgery; Engineering, Biomedical

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.