Abstract
Breast carcinoma is the most common malignancy in women. The progression of tumor is associated with overexpression of inhibitors of apoptosis proteins (IAPs) such as survivin and multidrug resistant P-glycoprotein (P-gp). PI3K/Akt pathway is involved in cell cycle progression, apoptosis and neoplastic transformation. PI3K/Akt has been shown to regulate survivin in breast cancer. The aim of this study was to investigate the expression of survivin and P-gp, the modulation of survivin by P-gp in PI3K/Akt during the progression of drug resistance (MDR) in MCF-7 breast cancer cells and adriamycin (ADR)-resistant MCF-7/ADR cells. The expression of survivin and P-gp in MCF-7/ADR cells were higher than that of the MCF-7 cells using RT-PCR and Western blot analysis. Survivin transcription was associated with P-glycoprotein/MDR1 overexpression using promoter activity analysis. LY294002, specific inhibitor of PI3K could suppress survivin and P-gp expression, decreased survivin promoter activity and enhanced cell sensitivity to drugs. This study shows survivin transcription was associated with P-glycoprotein/MDR1 overexpression, PI3k/Akt pathway was involved in P-glycoprotein/MDR1 associated survivin transcription activity in the multidrug resistant MCF-7 breast cancer 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 / antagonists & inhibitors
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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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Blotting, Western
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Cell Line, Tumor
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Chromones / pharmacology
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Dose-Response Relationship, Drug
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Doxorubicin / pharmacology
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Drug Resistance, Multiple / genetics*
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Drug Resistance, Neoplasm / genetics*
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins / genetics*
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Microtubule-Associated Proteins / metabolism
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Morpholines / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Promoter Regions, Genetic
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Survivin
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Transcription, Genetic*
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Transfection
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Up-Regulation
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Verapamil / pharmacology
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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BIRC5 protein, human
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Chromones
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Survivin
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Doxorubicin
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Verapamil
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Proto-Oncogene Proteins c-akt