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Cross-Resistance to Methotrexate and Metals in Human Cisplatin-resistant Cell Lines Results from a Pleiotropic Defect in Accumulation of These Compounds Associated with Reduced Plasma Membrane Binding Proteins

Laboratory of Cell Biology [D-w. S., M. M. G.] and Laboratory of Molecular Biology [I. P.], National Cancer Institute, NIH, Bethesda, Maryland 20892-4255

Cross-resistance to a wide array of toxic chemicals is a common phenomenon in cisplatin-resistant cell lines. In this study, two independently isolated cisplatin-resistant cell lines derived from a human hepatoma and a cervical adenocarcinoma were shown to be cross-resistant to methotrexate (MTX) and several metal salts, such as sodium arsenite, sodium arsenate, antimony potassium tartrate, and cadmium chloride. A pleiotropic defect resulting in reduced accumulation of cisplatin, ³[H]MTX, ⁷³As³⁺, and ⁷³As⁵⁺ was found in both cisplatin-resistant cell lines. Analysis by immunoblot, indirect immunofluorescence, and Northern hybridization showed dramatically reduced expression of the folate binding protein that mediates MTX uptake in both human cisplatin-resistant cell lines. By photoaffinity labeling with UV irradiation, specific binding proteins of M_r 230,000 and M_r 48,000 for ⁷³As³⁺ and M_r 190,000 for ⁷³As⁵⁺ were found in enriched plasma membrane of both human cisplatin-sensitive parental cell lines. Expression of these specific binding proteins was decreased in cells selected for cisplatin resistance. A protein band at M_r 36,000 that binds to ⁷³As³⁺ was overexpressed in both human cisplatin-resistant cell lines. The finding of loss of distinct binding proteins for MTX, arsenate, and arsenite in association with decreased accumulation of these agents in cisplatin-resistant cells suggests a pleiotropic, possibly regulatory, alteration in these cells.

¹ To whom requests for reprints should be addressed, at Laboratory of Cell Biology, National Cancer Institute, NIH, Building 37, Room 1B22, 37 Convent Dr., MSC 4255, National Cancer Institute, Bethesda, MD 20892-4255. Phone: (301) 496-1530; Fax: (301) 402-0450.

Received 6/30/97. Accepted 11/12/97.

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