The topoisomerase II–Hsp90 complex: A new chemotherapeutic target?

Barker, Catherine R., Hamlett, Jane, Pennington, Stephen R., Burrows, Francis, Lundgren, Karen, Lough, Rachel, Watson, Alastair J M ORCID: https://orcid.org/0000-0003-3326-0426 and Jenkins, John R. (2006) The topoisomerase II–Hsp90 complex: A new chemotherapeutic target? International Journal of Cancer, 118 (11). pp. 2685-2693. ISSN 0020-7136

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Abstract

The modulation of DNA topology by topoisomerase II plays a crucial role during chromosome condensation and segregation in mitosis and has thus become a highly attractive target for chemotherapeutic drugs. However, these drugs are highly toxic, and so new approaches are required. One such strategy is to target topoisomerase II-interacting proteins. Here we report the identification of potential topoisomerase II-associated proteins using immunoprecipitation, followed by 1-D and 2-D gel electrophoresis and MALDI-TOF mass spectrometry. A total of 23 proteins were identified and, of these, 17 were further validated as topoisomerase IIα-associated proteins by coimmunoprecipitation and Western blot. Six of the interacting proteins were cellular chaperones, including 3 members of the heat shock protein-90 (Hsp90) family, and so the effect of Hsp90 modulation on the antitumor activity of topoisomerase II drugs was tested using the sulforhodamine B assay, clonogenic assays and a xenograft model. The Hsp90 inhibitors geldanamycin, 17-AAG (17-allylamino-17-demethoxygeldanamycin) and radicicol significantly enhanced the activity of the topoisomerase II poisons etoposide and mitoxantrone in vitro and in vivo. Thus, our method of identifying topoisomerase II-interacting proteins appears to be effective, and at least 1 novel topoisomerase IIα-associated protein, Hsp90, may represent a valid drug target in the context of topoisomerase II-directed chemotherapy.

Item Type:	Article
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups:	Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Depositing User:	Rhiannon Harvey
Date Deposited:	14 Jul 2011 08:20
Last Modified:	20 Aug 2023 00:37
URI:	https://ueaeprints.uea.ac.uk/id/eprint/33689
DOI:	10.1002/ijc.21717

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