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

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dc.contributor.authorPark, Jung-Hyun-
dc.contributor.authorJong, Hyun-Soon-
dc.contributor.authorKim, Sang Gyun-
dc.contributor.authorJung, Yeonjoo-
dc.contributor.authorLee, Keun-Wook-
dc.contributor.authorLee, Ju-Hee-
dc.contributor.authorKim, Dae-Kee-
dc.contributor.authorBang, Yung-Jue-
dc.contributor.authorKim, Tae-You-
dc.date.accessioned2010-01-08T08:28:49Z-
dc.date.available2010-01-08T08:28:49Z-
dc.date.issued2007-09-14-
dc.identifier.citationJ Mol Med. 2008 Jan;86(1):117-28. Epub 2007 Sep 13.en
dc.identifier.issn1432-1440 (Electronic)-
dc.identifier.urihttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17851643-
dc.identifier.urihttps://hdl.handle.net/10371/29074-
dc.description.abstractThe 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.en
dc.language.isoen-
dc.publisherSpringer Verlagen
dc.subjectAntineoplastic Agentsen
dc.subjectBiphenyl Compounds/pharmacologyen
dc.subjectCell Death/drug effectsen
dc.subjectCell Line, Tumoren
dc.subjectEnzyme Inhibitors/*pharmacologyen
dc.subjectHSP70 Heat-Shock Proteins/metabolismen
dc.subjectHSP90 Heat-Shock Proteins/metabolismen
dc.subjectHistone Deacetylases/*antagonists & inhibitorsen
dc.subjectHumansen
dc.subjectHydroxamic Acids/pharmacologyen
dc.subjectProtein-Serine-Threonine Kinases/drug effects/*metabolismen
dc.subjectPyrrolidines/pharmacologyen
dc.subjectStomach Neoplasms/drug therapy/pathologyen
dc.titleInhibitors of histone deacetylases induce tumor-selective cytotoxicity through modulating Aurora-A kinaseen
dc.typeArticleen
dc.contributor.AlternativeAuthor박중현-
dc.contributor.AlternativeAuthor종현순-
dc.contributor.AlternativeAuthor김상균-
dc.contributor.AlternativeAuthor정연주-
dc.contributor.AlternativeAuthor이근욱-
dc.contributor.AlternativeAuthor이주희-
dc.contributor.AlternativeAuthor김대기-
dc.contributor.AlternativeAuthor방영주-
dc.contributor.AlternativeAuthor김태유-
dc.identifier.doi10.1007/s00109-007-0260-8-
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Program in Cancer Biology (협동과정-종양생물학전공)Journal Papers (저널논문_협동과정-종양생물학전공)
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