Abstract
Multidrug resistance-associated proteins (MRPs) may mediate multidrug resistance in tumor cells. Using a gene array analysis, we have identified MRP4 as an androgen receptor (AR)-regulated gene. Dihydrotestosterone induced MRP4 expression in both androgen-dependent and -independent LNCaP cells, whereas there was little detectable expression in PC-3 or normal prostate epithelial cells. Disruption of MRP4 expression renders LNCaP cells more sensitive to the cytotoxic effects of methotrexate but not etoposide. Analysis of human tissues showed detectable MRP4 expression only in metastatic prostate cancer. These results suggest that AR induction of MRP4 mediates resistance of PC cells to nucleotide-based chemotherapeutic drugs.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics*
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Adenocarcinoma / pathology
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Antimetabolites, Antineoplastic / pharmacology
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Dihydrotestosterone / pharmacology*
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Gene Deletion
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Gene Expression Regulation, Neoplastic / drug effects*
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Humans
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Male
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Methotrexate / pharmacology
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Multidrug Resistance-Associated Proteins / genetics*
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Multidrug Resistance-Associated Proteins / metabolism
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / pathology
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Receptors, Androgen / physiology
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Tumor Cells, Cultured
Substances
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ABCC4 protein, human
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Antimetabolites, Antineoplastic
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Multidrug Resistance-Associated Proteins
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Receptors, Androgen
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Dihydrotestosterone
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Methotrexate