Inhibition of clathrin by pitstop 2 activates the spindle assembly checkpoint and induces cell death in dividing HeLa cancer cells

Molecular Cancer

Research

Adam McCluskey¹  Phillip J Robinson²  Charlotte M Smith²  Megan Chircop³  Volker Haucke⁴ 

[1] Chemistry, School of Environmental & Life Sciences, The University of Newcastle, 2308, Callaghan, NSW, Australia;Children's Medical Research Institute, The University of Sydney, 214 Hawkesbury Road, 2145, Westmead, NSW, Australia;Children's Medical Research Institute, The University of Sydney, 214 Hawkesbury Road, 2145, Westmead, NSW, Australia;Children’s Medical Research Institute, Locked Bag 23, 2145, Wentworthville, NSW, Australia;Institute of Chemistry and Biochemistry & Neurocure Cluster of Excellence, Freie Universität Berlin, 14195, Berlin, Germany;Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin-Buch, Germany;

关键词: Clathrin;    Pitstop;    Spindle assembly checkpoint;    Metaphase;    Cell death;    Cancer;   

DOI  :  10.1186/1476-4598-12-4

 received in 2012-09-03, accepted in 2013-01-03,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundDuring metaphase clathrin stabilises the mitotic spindle kinetochore(K)-fibres. Many anti-mitotic compounds target microtubule dynamics. Pitstop 2™ is the first small molecule inhibitor of clathrin terminal domain and inhibits clathrin-mediated endocytosis. We investigated its effects on a second function for clathrin in mitosis.ResultsPitstop 2 did not impair clathrin recruitment to the spindle but disrupted its function once stationed there. Pitstop 2 trapped HeLa cells in metaphase through loss of mitotic spindle integrity and activation of the spindle assembly checkpoint, phenocopying clathrin depletion and aurora A kinase inhibition.ConclusionsPitstop 2 is therefore a new tool for investigating clathrin spindle dynamics. Pitstop 2 reduced viability in dividing HeLa cells, without affecting dividing non-cancerous NIH3T3 cells, suggesting that clathrin is a possible novel anti-mitotic drug target.

【 授权许可】

Unknown   
© Smith et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.