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Inhibitors of histone deacetylases induce tumor-selective cytotoxicity through modulating Aurora-A kinase
Cited 43 time in
Web of Science
Cited 41 time in Scopus
- Authors
- Issue Date
- 2007-09-14
- Publisher
- Springer Verlag
- Citation
- J Mol Med. 2008 Jan;86(1):117-28. Epub 2007 Sep 13.
- Keywords
- Antineoplastic Agents ; Biphenyl Compounds/pharmacology ; Cell Death/drug effects ; Cell Line, Tumor ; Enzyme Inhibitors/*pharmacology ; HSP70 Heat-Shock Proteins/metabolism ; HSP90 Heat-Shock Proteins/metabolism ; Histone Deacetylases/*antagonists & inhibitors ; Humans ; Hydroxamic Acids/pharmacology ; Protein-Serine-Threonine Kinases/drug effects/*metabolism ; Pyrrolidines/pharmacology ; Stomach 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
https://hdl.handle.net/10371/29074
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