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Down-Regulation and Altered Localization of -Catenin in Cisplatin-Resistant Adenocarcinoma Cells

Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Resistance to cisplatin, one of the most widely used anticancer chemotherapeutic agents, is a major clinical problem. There is no effective way to predict development of cisplatin resistance in cancers. As determined by reverse transcription-polymerase chain reaction and Western blotting, the expression of -catenin, an adherens junction protein, was decreased in KB-CP20 and 7404-CP20 cells compared with parental-sensitive cells. Short-term treatment with cisplatin of the parental cells resulted in proteolysis of -catenin as evaluated in membrane pellet preparations, and the extent of cleavage increased as cisplatin concentration was raised from 1 to 5 µg/ml during 1 h of treatment. Uncleaved cytoplasmic -catenin increased under the same conditions. These biochemical results were supported by confocal microscopy, which showed a loss of -catenin from adherens plaques after cisplatin treatment. Cleavage of -catenin was specific to cisplatin treatment in that cleavage did not occur after treatment with doxorubicin and cytosine arabinoside. Pretreatment of KB and 7404 cells with cisplatin for 1 h resulted in reduced uptake of [¹⁴C]carboplatin, suggesting that the biochemical changes induced by cisplatin treatment, including cleavage of -catenin, could affect the ability of cells to internalize platinum compounds. Cells transfected with the -catenin gene are sensitive to cisplatin compared with cells transfected with a control vector. Our data suggest that proteolysis and altered localization of -catenin are early markers for the response of cells to cisplatin, and reduced levels of -catenin in resistant cells may indicate an important role for -catenin in mediating or modulating the toxicity of cisplatin in cancer cells.

Received December 12, 2003; accepted February 4, 2004.

Address correspondence to: Dr. Michael M. Gottesman, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, 37 Convent Drive, Room 1A09, Bethesda, MD 20892-4254. E-mail: mgottesman{at}nih.gov

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