title: Downregulation of JNK/SAPK activity is associated with the cross-resistance to P-glycoprotein-unrelated drugs in multidrug-resistant FM3A/M cells overexpressing P-glycoprotein.
abstract: In the present study, cross-drug resistance in multidrug-resistant (MDR) cells, which overexpress P-glycoprotein (Pgp), a mdr1 gene product, against Pgp-unrelated drugs, and its relevance to c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) activity were examined. The multidrug-resistant FM3A/M cells overexpressing Pgp were resistant to apoptotic cell death induced either by Pgp-related drugs including vincristine and vinblastine, which are pumped out by Pgp, or by the Pgp-unrelated drugs including 5'-fluorouracil (5-FU) and bleomycin, which are not targets for Pgp, compared with the parental FM3A cells. Verapamil reversed the resistance of FM3A/M cells to apoptosis induced by the Pgp-related drugs but not that induced by the Pgp-unrelated drugs. Interestingly, FM3A/M cells have shown significantly lower basal and drug-stimulated JNK/SAPK activities than FM3A cells. After transfection with pEBG-SEK or pEBG-SAPK constructs, FM3A/M cells recovered the basal and Pgp-unrelated drug-stimulated activities of JNK/SAPK and the susceptibility to Pgp-unrelated drug-induced apoptotic cell death comparable to those of FM3A cells. Furthermore, FM3A cells became resistant to apoptotic cell death induced by vincristine and 5-FU after transfection with pEBG-SEK(K --> R), a dominant negative inhibitory mutant of SEK. These results suggest that downregulation of JNK/SAPK activity appears to confer on Pgp-associated FM3A/M cells a cross-resistance to Pgp-unrelated drugs.
authors.affiliation: Department of Biochemistry, Pusan National University, Pusan, 602-739, Korea. kcdshbw@hyowon.pusan.ac.kr
authors.forename: C D
authors.initials: CD
authors.lastname: Kang
authors.forename: B K
authors.initials: BK
authors.lastname: Ahn
authors.forename: C S
authors.initials: CS
authors.lastname: Jeong
authors.forename: K W
authors.initials: KW
authors.lastname: Kim
authors.forename: H J
authors.initials: HJ
authors.lastname: Lee
authors.forename: S D
authors.initials: SD
authors.lastname: Yoo
authors.forename: B S
authors.initials: BS
authors.lastname: Chung
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001761:Bleomycin / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects*; D018432:Drug Resistance, Multiple / Q000502:physiology*; D005260:Female; D005472:Fluorouracil / Q000633:toxicity; D019450:Genes, MDR; D048031:JNK Mitogen-Activated Protein Kinases; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000493:pharmacokinetics / Q000633:toxicity; D014750:Vincristine / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D001761:Bleomycin; D014750:Vincristine; D014747:Vinblastine; D014700:Verapamil; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D005472:Fluorouracil