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Carcinogenesis Advance Access published online on April 4, 2008
Carcinogenesis, 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 Kang1,2,3

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

3 To whom correspondence should be addressed: Tel: 62-230-6368; Fax: 62-222-5414; E-mail: kwkang{at}chosun.ac.kr

The development of multidrug resistance 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 C/EBPβ 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 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.

Key Words: chemoresistance • adriamycin-resistant breast cancer • MDR1 • FoxO1

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


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