Abstract
This study investigated whether P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) are linked in terms of expression. RT-PCR and Western blot analyses showed that the lung cancer cell line SK-MES-1/WT expressed BCRP. In a drug-free state, BCRP expression was significantly down-regulated in doxorubicin-resistant SK-MES-1/DX1000 cells overexpressing Pgp. Pharmacological inhibitors (PSC833 or verapamil) or siRNA for Pgp inhibited the down-regulation of BCRP, which was confirmed by confocal microscopy. PSC833 induced the phosphorylation of c-Jun NH2-terminal kinase (JNK) and c-Jun, while the JNK inhibitor SP600125 inhibited this effect. Dominant negative c-Jun decreased the expression of BCRP, but increased that of Pgp. These results indicate that Pgp down-regulates BCRP expression in a drug-free state in which JNK/c-Jun is involved.
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, Member 1 / genetics
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism*
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Anthracenes / pharmacology
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Antibiotics, Antineoplastic / pharmacology
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Cell Line, Tumor
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Cyclosporins / pharmacology
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Down-Regulation
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Doxorubicin / pharmacology
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Drug Resistance, Neoplasm*
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Humans
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
Substances
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Anthracenes
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Antibiotics, Antineoplastic
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Cyclosporins
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Neoplasm Proteins
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pyrazolanthrone
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Doxorubicin
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JNK Mitogen-Activated Protein Kinases
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valspodar