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Inhibitors of histone deacetylases induce tumor-selective cytotoxicity through modulating Aurora-A kinase

Cited 42 time in Web of Science Cited 40 time in Scopus
Authors
Park, Jung-Hyun; Jong, Hyun-Soon; Kim, Sang Gyun; Jung, Yeonjoo; Lee, Keun-Wook; Lee, Ju-Hee; Kim, Dae-Kee; Bang, Yung-Jue; Kim, Tae-You
Issue Date
2007-09-14
Publisher
Springer Verlag
Citation
J Mol Med. 2008 Jan;86(1):117-28. Epub 2007 Sep 13.
Keywords
Antineoplastic AgentsBiphenyl Compounds/pharmacologyCell Death/drug effectsCell Line, TumorEnzyme Inhibitors/*pharmacologyHSP70 Heat-Shock Proteins/metabolismHSP90 Heat-Shock Proteins/metabolismHistone Deacetylases/*antagonists & inhibitorsHumansHydroxamic Acids/pharmacologyProtein-Serine-Threonine Kinases/drug effects/*metabolismPyrrolidines/pharmacologyStomach Neoplasms/drug therapy/pathology
Abstract
The molecular basis of the antitumor selectivity of histone deacetylase inhibitors (HDIs) remains unclear. Centrosomal Aurora-A kinase regulates chromosomal segregation during mitosis. The overexpression or amplification of Aurora-A leads to genetic instability, and its inhibition has shown significant antitumor effects. In this paper, we report that structurally related hydroxamate LAQ824 and SK-7068 induce tumor-selective mitotic defects by depleting Aurora-A. We found that HDI-treated cancer cells, unlike nontransformed cells, exhibit defective mitotic spindles. After HDI, Aurora-A was selectively downregulated in cancer cells, whereas Aurora-B remained unchanged in both cancer and nontransformed cells. LAQ824 or SK-7068 treatment inhibited histone deacetylase (HDAC) 6 present in Aurora-A/heat shock protein (Hsp) 90 complex. Inhibition of HDAC6 acetylated Hsp90 and resulted in dissociation of acetylated Hsp90 from Aurora-A. As a result, Hsp70 binding to Aurora-A was enhanced in cancer cells, leading to proteasomal degradation of Aurora-A. Overall, these provide a novel molecular basis of tumor selectivity of HDI. LAQ824 and SK-7068 might be more effective HDIs in cancer cells with Aurora-A overexpression.
ISSN
1432-1440 (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17851643

http://hdl.handle.net/10371/29074
DOI
https://doi.org/10.1007/s00109-007-0260-8
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College of Medicine/School of Medicine (의과대학/대학원)Program in Cancer Biology (협동과정-종양생물학전공)Journal Papers (저널논문_협동과정-종양생물학전공)
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