Abstract
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 beta-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
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Antibiotics, Antineoplastic / pharmacology*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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CCAAT-Enhancer-Binding Protein-beta / genetics
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CCAAT-Enhancer-Binding Protein-beta / metabolism
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Cell Nucleus / metabolism
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Doxorubicin / pharmacology*
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Drug Resistance, Multiple
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Drug Resistance, Neoplasm*
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Electrophoretic Mobility Shift Assay
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Forkhead Box Protein O1
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Forkhead Transcription Factors / antagonists & inhibitors
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Gene Expression Regulation, Neoplastic
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Humans
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Immunoblotting
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Insulin / pharmacology
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Plasmids
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Pregnane X Receptor
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Promoter Regions, Genetic / genetics
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / pharmacology
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Receptors, Steroid / genetics
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Receptors, Steroid / metabolism
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Transcriptional Activation / drug effects
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Tumor Cells, Cultured
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Antibiotics, Antineoplastic
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CCAAT-Enhancer-Binding Protein-beta
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FOXO1 protein, human
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Insulin
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Pregnane X Receptor
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RNA, Messenger
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RNA, Small Interfering
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Receptors, Steroid
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Doxorubicin