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Research Articles: Therapeutics, Targets, and Development

Doxorubicin activates FOXO3a to induce the expression of multidrug resistance gene ABCB1 (MDR1) in K562 leukemic cells

¹ Department of Oncology, Cancer Research UK Labs; ² Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital Campus, London, United Kingdom and ³ Department of Dermatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan

Requests for reprints: Eric W-F. Lam, Department of Oncology, Cancer Research UK Labs, MRC Cyclotron Building, Du Cane Road, London W12 0NN, United Kingdom. Phone: 44-20-8383-5829; Fax: 44-20-8383-5830. E-mail: eric.lam{at}imperial.ac.uk

Abstract

Using the doxorubicin-sensitive K562 cell line and the resistant derivative lines KD30 and KD225 as models, we found that acquisition of multidrug resistance (MDR) is associated with enhanced FOXO3a activity and expression of ABCB1 (MDR1), a plasma membrane P-glycoprotein that functions as an efflux pump for various anticancer agents. Furthermore, induction of ABCB1 mRNA expression on doxorubicin treatment of naive K562 cells was also accompanied by increased FOXO3a activity. Analysis of transfected K562, KD30, and KD225 cells in which FOXO3a activity can be induced by 4-hydroxytamoxifen showed that FOXO3a up-regulates ABCB1 expression at protein, mRNA, and gene promoter levels. Conversely, silencing of endogenous FOXO3a expression in KD225 cells inhibited the expression of this transport protein. Promoter analysis and chromatin immunoprecipitation assays showed that FOXO3a regulation of ABCB1 expression involves binding of this transcription factor to the proximal promoter region. Moreover, activation of FOXO3a increased ABCB1 drug efflux potential in KD30 cells, whereas silencing of FOXO3a by siRNA significantly reduced ABCB1 drug efflux ability. Together, these findings suggest a novel mechanism that can contribute towards MDR, involving FOXO3a as sensor for the cytotoxic stress induced by anticancer drugs. Although FOXO3a may initially trigger a program of cell cycle arrest and cell death in response to doxorubicin, sustained FOXO3a activation promotes drug resistance and survival of cells by activating ABCB1 expression. [Mol Cancer Ther 2008;7(3):670–8]

Grant support: Cancer Research UK (E.W-F. Lam, R.C-Y. Hui, and S.S. Myatt) and Association for International Cancer Research (E.W-F. Lam and R.E. Francis).

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.

⁴ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org).

Received 6/12/07; revised 12/20/07; accepted 1/ 9/08.

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