Journal Article

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

Chang-Yeob Han, Kyoung-Bin Cho, Hong-Seok Choi, Hyo-Kyung Han and Keon-Wook Kang

in Carcinogenesis

Volume 29, issue 9, pages 1837-1844
Published in print September 2008 | ISSN: 0143-3334
Published online April 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn092
Role of FoxO1 activation in MDR1 expression in adriamycin-resistant breast cancer cells

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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.

Journal Article.  4534 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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