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Carcinogenesis Advance Access originally published online on April 4, 2008
Carcinogenesis 2008 29(9):1837-1844; doi:10.1093/carcin/bgn092
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Role of FoxO1 activation in MDR1 expression in adriamycin-resistant breast cancer cells

Chang-Yeob Han1,2, Kyoung-Bin Cho1,2, Hong-Seok Choi2, Hyo-Kyung Han1,2 and Keon-Wook Kang1,2,*

1 BK21 Project Team, College of Pharmacy, Chosun University, Gwangju 501-759, South Korea
2 Department of Pharmacy, College of Pharmacy, Chosun University, Gwangju 501-759, South Korea

* To whom correspondence should be addressed. Tel: +82 62 230 6368; Fax: +82 62 222 5414; Email: kwkang{at}chosun.ac.kr

The development of multidrug resistance 1 (MDR1) can be mediated by a number of different mechanisms but elevated gene expression of MDR1 (P-glycoprotein) has often been a major cause of chemoresistance in many cancer cells. Therefore, the present study aimed to investigate the role of forkhead box-containing protein, O subfamily (FoxO), transcription factors in regulating the MDR1 gene expression. The proximal promoter region of the human MDR1 contained a putative FoxO-binding site, which partially overlapped with the enhancer/enhancer-binding protein β-binding region. Gel shift and immunoblot analysis of subcellular fractions revealed that nuclear levels of FoxO1 and its DNA-binding activity were selectively enhanced in MCF-7/ADR cells, which was reversed by a FoxO1 antibody. Reporter gene assays showed that the transcription of MDR1 gene is stimulated by FoxO1 overexpression. Moreover, both MDR1 expression and doxorubicin resistance in MCF-7/ADR cells were reversed by FoxO1 small interfering RNA (siRNA). The MDR1 expression in MCF-7/ADR cells was also inhibited by insulin, a functional FoxO1 inactivator. In conclusion, FoxO1 is a novel transcriptional activator of MDR1 and is crucial for MDR1 induction in MCF-7/ADR cells.

Abbreviations: C/EBP, CCAAT/enhancer-binding protein; Dox, doxorubicin; EDTA, ethylenediaminetetraacetic acid; FHRE, forkhead response element; FoxO, forkhead box-containing protein, O subfamily; MDR1, multidrug resistance 1; PXR, pregnane X receptor; R-123, rhodamine-123; siRNA, small interfering RNA

Received January 7, 2008; revised March 19, 2008; accepted March 29, 2008.


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