title: Mislocalization of membrane proteins associated with multidrug resistance in cisplatin-resistant cancer cell lines.
abstract: The accumulation of [(14)C]carboplatin and [(3)H]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 (35)S-methionine and (35)S-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.
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-4254, USA.
authors.forename: Xing-Jie
authors.initials: XJ
authors.lastname: Liang
authors.forename: Ding-Wu
authors.initials: DW
authors.lastname: Shen
authors.forename: Susan
authors.initials: S
authors.lastname: Garfield
authors.forename: Michael M
authors.initials: MM
authors.lastname: Gottesman
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001710:Biotin / Q000031:analogs & derivatives* / Q000378:metabolism; D002250:Carbon Radioisotopes; D016190:Carboplatin / Q000493:pharmacokinetics; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D003545:Cysteine / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D058973:Folate Receptors, GPI-Anchored; D006367:HeLa Cells; D006801:Humans; D007624:KB Cells; D008247:Lysosomes / Q000378:metabolism; D008715:Methionine / Q000378:metabolism; D008727:Methotrexate / Q000493:pharmacokinetics; D011956:Receptors, Cell Surface; D013388:Succinimides / Q000378:metabolism; D013462:Sulfur Radioisotopes; D014283:Triiodobenzoic Acids / Q000737:chemistry; D014316:Tritium
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D058973:Folate Receptors, GPI-Anchored; C000717247:HSPA5 protein, human; D011956:Receptors, Cell Surface; D013388:Succinimides; D013462:Sulfur Radioisotopes; D014283:Triiodobenzoic Acids; C065130:sulfo-N-hydroxysuccinimide-biotin; D014316:Tritium; D001710:Biotin; D008715:Methionine; D016190:Carboplatin; C044834:iodixanol; D003545:Cysteine; D002945:Cisplatin; D008727:Methotrexate