This Article Full Text Full Text (PDF) All Versions of this Article: 1535-7163.MCT-06-0417v1 6/1/299    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kamada, M. Articles by Gleave, M. Search for Related Content PubMed PubMed Citation Articles by Kamada, M. Articles by Gleave, M.

Research Articles: Therapeutics, Targets, and Development

Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells

¹ The Prostate Centre, Vancouver General Hospital and ² Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada

Requests for reprints: Martin Gleave, The Prostate Centre, University of Columbia, Vancouver Hospital, 2660-Oak Street, Vancouver, BC, Canada V6H-3Z6. Phone: 604-875-5003; Fax: 604-875-5604. E-mail: m.gleave{at}ubc.ca

Abstract

Heat shock protein 27 (Hsp27) is a cytoprotective chaperone that is phosphoactivated during cell stress that prevents aggregation and/or regulate activity and degradation of certain client proteins. Recent evidence suggests that Hsp27 may be involved in tumor progression and the development of treatment resistance in various tumors, including bladder cancer. The purpose of this study was to examine, both in vitro and in vivo, the effects of overexpression of Hsp27 and, correspondingly, the down-regulation of Hsp27 using small interfering (si) RNA and OGX-427, a second-generation antisense oligonucleotide targeting Hsp27. Hsp27 overexpression increased UMUC-3 cell growth and resistance to paclitaxel. Both OGX-427 and Hsp27 siRNA decreased Hsp27 protein and mRNA levels by >90% in a dose- and sequence-specific manner in human bladder cancer UMUC-3 cells. OGX-427 or Hsp27 siRNA treatment induced apoptosis and enhanced sensitivity to paclitaxel in UMUC-3 cells. In vivo, OGX-427 significantly inhibited tumor growth in mice, enhanced sensitivity to paclitaxel, and induced significantly higher levels of apoptosis compared with xenografts treated with control oligonucleotides. Collectively, these findings suggest that Hsp27 knockdown with OGX-427 and combined therapy with paclitaxel could be a novel strategy to inhibit the progression of bladder cancer. [Mol Cancer Ther 2007;6(1):299–308]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received 7/18/06; revised 9/28/06; accepted 11/27/06.