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Identification of Cytoskeletal [¹⁴C]Carboplatin-Binding Proteins Reveals Reduced Expression and Disorganization of Actin and Filamin in Cisplatin-Resistant Cell Lines

Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (D.-W.S., X.-J.L., M.M.G.); and Protein Core Facility, Columbia University, New York, New York (M.A.G.)

Cisplatin resistant (CP-r) cells often show decreased uptake of cisplatin in association with reduced cell surface proteins and decreased endocytosis. In this report, two major [¹⁴C]carboplatin-binding proteins were identified as filamin and actin by photoaffinity labeling and mass spectrometry. Decreased expression of these two proteins was found in two different human CP-r cell lines (KB-CP20 and 7404-CP20), in comparison with their parental cell lines (KB-3-1 and BEL-7404), respectively. Disorganization of -actin and filamin 250 and 90 was also detected in these CP-r cells by confocal microscopy. Transfection of a wild-type actin-enhanced green fluorescent protein (EGFP) expression vector into 7404-CP20 cells resulted in a nonfilamentous actin-EGFP distribution compared with a normal distribution in the cisplatin-sensitive BEL-7404 cells, suggesting that cytoskeletal organization is disturbed in the CP-r cells. The identification of actin and filamin as [¹⁴C]carboplatin-binding proteins and decreased expression and disorganization of several cytoskeletal proteins in CP-r cells provide a molecular and cellular basis for the known defect in endocytosis in these cells.

Received January 27, 2004; accepted June 10, 2004.

Address correspondence to: 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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