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Mislocalization of Membrane Proteins Associated with Multidrug Resistance in Cisplatin-resistant Cancer Cell Lines¹

Laboratory of Cell Biology [X-J. L., D-W. S., M. M. G.] and Laboratory of Experimental Carcinogenesis [S. G.], Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4254

The accumulation of [¹⁴C]carboplatin and [³H]methotrexate is reduced in single-step KB epidermoid adenocarcinoma (KB-CP) cells, which are cross-resistant to carboplatin, methotrexate, and sodium arsenite. In these KB-CP cells, multidrug resistance is accompanied by mislocalization of multidrug resistance associated protein (MRP) 1 and other membrane proteins such as folate-binding protein. MRP1 was not decreased in amount in single-step variants but accumulates in a cytoplasmic fraction, and its apparent molecular weight was altered probably because of reduced glycosylation in resistant cells. This low-density compartment was partially labeled with antibodies to lectin-GSII (a Golgi marker) and Bip/GRP78 (an endoplasmic reticulum marker). Pulse-chase labeling of MRP1 with ³⁵S-methionine and ³⁵S-cysteine and pulse-chase biotinylation of cell surface MRP1 suggests that membrane protein mislocalization is caused mainly by a defect of plasma membrane protein recycling, manifested also as a defect in acidification of lysosomes. The reduced accumulation of cytotoxic compounds in the KB-CP cells is presumed to result from the failure of carrier proteins and/or transporters to localize to the plasma membrane.

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