Abstract
P-glycoprotein (P-gp)-mediated multi-drug resistance (MDR) is a major barrier to the effective chemotherapy of many cancers. Recent studies have shown that inhibition of the PI3K/Akt signalling pathway can reverse P-gp-mediated MDR. We investigated the expression of activated Akt (p-Akt) in 124 human gastric carcinoma tissue samples. Ubiquitous p-Akt expression was recorded in the majority (88/124). There was a significant correlation between p-Akt expression and the expression of P-gp. In the adriamycin-resistant MDR gastric carcinoma cell line SGC7901/ADR, p-Akt expression was increased in comparison with the parental cell line SGC7901. Treatment of SGC7901/ADR cells with the PI3K inhibitor LY294002 reduced the expression of both p-Akt and P-gp. To explore the role of ubiquitin ligase Cbl-b in this regulatory pathway, SGC7901/ADR cells were transfected with a plasmid overexpressing wild-type Cbl-b. This down-regulated the expression of both p-Akt and P-gp. Furthermore, resistance to chemotherapeutic drugs was partially reversed. These results demonstrate an important role for Cbl-b in reversing P-gp-mediated gastric cancer MDR through suppression of the PI3K/Akt signalling pathway and the down-regulation of P-gp expression.
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 / analysis
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
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Adaptor Proteins, Signal Transducing / analysis
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Adaptor Proteins, Signal Transducing / genetics*
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Adenocarcinoma / drug therapy
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Adenocarcinoma / metabolism*
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Adult
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Cell Line, Tumor
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Chromones / pharmacology
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Doxorubicin / analysis
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Doxorubicin / pharmacology
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Drug Resistance, Multiple*
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Female
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Flow Cytometry
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Gene Expression / drug effects
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Gene Expression Profiling
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Humans
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Immunohistochemistry
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Inhibitory Concentration 50
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Male
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Middle Aged
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Morpholines / pharmacology
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Oligonucleotide Array Sequence Analysis
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Oncogene Protein v-akt / genetics
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Oncogene Protein v-akt / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-cbl / analysis
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Proto-Oncogene Proteins c-cbl / genetics*
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Stomach Neoplasms / drug therapy
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Stomach Neoplasms / metabolism*
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Transfection / methods
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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Chromones
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Morpholines
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Phosphoinositide-3 Kinase Inhibitors
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Doxorubicin
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CBLB protein, human
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Proto-Oncogene Proteins c-cbl
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Oncogene Protein v-akt