Unstable expression of the multi-drug-resistant phenotype in Chinese hamster ovary cells resistant to okadaic acid.
A Chinese hamster ovary cell line resistant to okadaic acid (OA), OAR2-3 has a mutation of the protein phosphatase (PP) 2A alpha gene and expresses a multi-drug resistance (MDR) phenotype. In the present work, we isolated two additional OA-resistant variants, also showing MDR with a cross-resistance profile similar to that of OAR2-3, and with increased and decreased expressions of the P-glycoprotein (Pgp) and DNA topoisomerase (topo) II protein, respectively. Unlike OAR2-3, however, they had no mutation in the same region of the PP2A alpha gene. Except for OA-resistance in OAR2-3, the MDR was found to decrease in the absence of OA, and this decrease was again associated with changes in topo II- and Pgp-expressions. Thus, we conclude that 1) OA regulates the expressions of Pgp and topo II positively and negatively, respectively, resulting in reversible expression of MDR irrespective of genetic changes and 2) in OAR2-3, the mutation in the PP2A alpha gene confers stable resistance to OA. The MDR was also linked with collateral sensitivity to some drugs, like cisplatin and nitrogen mustard.
Tohda
H
H
Department of Neurochemistry and Molecular Biology, Tohoku University, Sendai, Japan.
Takao
M
M
Kikuchi
A
A
Yasumoto
T
T
Yasui
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000818:Animals; D016466:CHO Cells / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism; D002469:Cell Separation; D006224:Cricetinae; D018432:Drug Resistance, Multiple / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D015870:Gene Expression / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D019319:Okadaic Acid / Q000494:pharmacology*; D010641:Phenotype; D017354:Point Mutation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D019319:Okadaic Acid