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Inhibitors of histone deacetylases induce tumor-selective cytotoxicity through modulating Aurora-A kinase
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Park, Jung-Hyun | - |
dc.contributor.author | Jong, Hyun-Soon | - |
dc.contributor.author | Kim, Sang Gyun | - |
dc.contributor.author | Jung, Yeonjoo | - |
dc.contributor.author | Lee, Keun-Wook | - |
dc.contributor.author | Lee, Ju-Hee | - |
dc.contributor.author | Kim, Dae-Kee | - |
dc.contributor.author | Bang, Yung-Jue | - |
dc.contributor.author | Kim, Tae-You | - |
dc.date.accessioned | 2010-01-08T08:28:49Z | - |
dc.date.available | 2010-01-08T08:28:49Z | - |
dc.date.issued | 2007-09-14 | - |
dc.identifier.citation | J Mol Med. 2008 Jan;86(1):117-28. Epub 2007 Sep 13. | en |
dc.identifier.issn | 1432-1440 (Electronic) | - |
dc.identifier.uri | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17851643 | - |
dc.identifier.uri | https://hdl.handle.net/10371/29074 | - |
dc.description.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. | en |
dc.language.iso | en | - |
dc.publisher | Springer Verlag | en |
dc.subject | Antineoplastic Agents | en |
dc.subject | Biphenyl Compounds/pharmacology | en |
dc.subject | Cell Death/drug effects | en |
dc.subject | Cell Line, Tumor | en |
dc.subject | Enzyme Inhibitors/*pharmacology | en |
dc.subject | HSP70 Heat-Shock Proteins/metabolism | en |
dc.subject | HSP90 Heat-Shock Proteins/metabolism | en |
dc.subject | Histone Deacetylases/*antagonists & inhibitors | en |
dc.subject | Humans | en |
dc.subject | Hydroxamic Acids/pharmacology | en |
dc.subject | Protein-Serine-Threonine Kinases/drug effects/*metabolism | en |
dc.subject | Pyrrolidines/pharmacology | en |
dc.subject | Stomach Neoplasms/drug therapy/pathology | en |
dc.title | Inhibitors of histone deacetylases induce tumor-selective cytotoxicity through modulating Aurora-A kinase | en |
dc.type | Article | en |
dc.contributor.AlternativeAuthor | 박중현 | - |
dc.contributor.AlternativeAuthor | 종현순 | - |
dc.contributor.AlternativeAuthor | 김상균 | - |
dc.contributor.AlternativeAuthor | 정연주 | - |
dc.contributor.AlternativeAuthor | 이근욱 | - |
dc.contributor.AlternativeAuthor | 이주희 | - |
dc.contributor.AlternativeAuthor | 김대기 | - |
dc.contributor.AlternativeAuthor | 방영주 | - |
dc.contributor.AlternativeAuthor | 김태유 | - |
dc.identifier.doi | 10.1007/s00109-007-0260-8 | - |
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