Abstract
In a past decade became evident that phosphatidylinositol-3-kinase controlled signal transduction cascade (PI3K/Akt/PTEN/mTOR) is implicated in resistance of tumor cells to anticancer drugs. Another well studied mechanism of multidrug resistance is associated with the activity of drug transporters of ABC superfamily (first of all P-glycoprotein (Pgp), MRP1, BCRP). Several mechanisms of cell defense can be turned on in one cell. The interconnections between different mechanisms involved in drug resistance are poorly studied. In the present study we used PC3 and DU145 human prostate cell lines to show that PTEN functional status determines level of cell resistance to some drugs, it correlates with expression level of MRP1 and BCRP proteins. We showed that Pgp is not involved in development of drug resistance in these cells. Transfection of PTEN into PTEN-deficient PC3 as well as rapamycin treatment caused the inhibition of PI3K/Akt/mTOR signaling and resulted in cell sensitization to the action of doxorubicin and vinblastine. We showed that PTEN transfection leads to the change in expression of MRP1 and BCRP. Our results show that in prostate cancer cells at least two mechanisms of drug resistance are interconnected. PTEN and mTOR signaling were shown: to be involved into regulation of MRP1 and BCRP.
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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Antibiotics, Antineoplastic / pharmacology
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Cell Line, Tumor
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Drug Resistance, Multiple* / drug effects
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Drug Resistance, Multiple* / genetics
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Drug Resistance, Neoplasm* / drug effects
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Drug Resistance, Neoplasm* / genetics
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Humans
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Male
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Multidrug Resistance-Associated Proteins / genetics
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Multidrug Resistance-Associated Proteins / metabolism
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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PTEN Phosphohydrolase / biosynthesis*
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PTEN Phosphohydrolase / genetics
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism*
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Signal Transduction* / drug effects
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Signal Transduction* / genetics
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Sirolimus / pharmacokinetics
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TOR Serine-Threonine Kinases
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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Antibiotics, Antineoplastic
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Multidrug Resistance-Associated Proteins
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Neoplasm Proteins
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Protein Kinases
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MTOR protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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PTEN Phosphohydrolase
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PTEN protein, human
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Sirolimus
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multidrug resistance-associated protein 1