title: Attenuated JNK signaling in multidrug-resistant leukemic cells. Dual role of MAPK in cell survival.
abstract: Having found previously that leukemic cells with multidrug resistant (MDR) phenotype, but not their sensitive counterparts, exhibit collateral sensitivity to cold stress in a P-gp-dependent manner, our aim was to study the signaling pathways involved in this phenomenon in sensitive (L1210) and resistant cells (L1210R and CBMC-6). It was observed that the acquisition of MDR phenotype by leukemic cells or their transfection with the extrussion pump, P-gp, modifies the activation profile and regulation of Mitogen-Activated Protein Kinases (MAPK) in cells exposed to low temperatures. More specifically, cold stress provoked the activation of c-Jun N-terminal kinase (JNK) in sensitive cells, while attenuated JNK signaling was observed in MDR cells. This effect was also observed, although with less intensity, in P-gp-transfected cells. Using pharmacological inhibitors to determine the role of MAPK in leukemic cell survival in physiological conditions or under cold stress, a dual temperature-dependent role was observed for JNK in MDR cell survival. At 37°C JNK is necessary for the survival of parental, resistant and P-gp-transfected cells; however, the use of inhibitors of either extracellular signal-regulated protein kinase (ERK) or JNK significantly counteracts cold-induced death of resistant and P-gp-transfected cells, supporting a role for ERK and JNK in cold-stress induced cell death. Finally, a connectivity model concerning MAPK is proposed, summarizing how cold stress and MDR-1 might trigger apoptosis in resistant cell lines. These findings on MDR cells may assist in the design of specific therapeutic strategies to complement current chemotherapy.
authors.affiliation: Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, Murcia Biohealth Research Institute-University of Murcia (IMIB-UMU), Regional Campus of International Excellence "Campus Mare Nostrum", 30100 Murcia, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Cerezo
authors.affiliation: Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, Murcia Biohealth Research Institute-University of Murcia (IMIB-UMU), Regional Campus of International Excellence "Campus Mare Nostrum", 30100 Murcia, Spain.
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Ruiz-Alcaraz
authors.affiliation: Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, Murcia Biohealth Research Institute-University of Murcia (IMIB-UMU), Regional Campus of International Excellence "Campus Mare Nostrum", 30100 Murcia, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Lencina-Guardiola
authors.affiliation: Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, Murcia Biohealth Research Institute-University of Murcia (IMIB-UMU), Regional Campus of International Excellence "Campus Mare Nostrum", 30100 Murcia, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Cánovas
authors.affiliation: Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, Murcia Biohealth Research Institute-University of Murcia (IMIB-UMU), Regional Campus of International Excellence "Campus Mare Nostrum", 30100 Murcia, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: García-Peñarrubia
authors.affiliation: Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, Murcia Biohealth Research Institute-University of Murcia (IMIB-UMU), Regional Campus of International Excellence "Campus Mare Nostrum", 30100 Murcia, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Martínez-López
authors.affiliation: Department of Biochemistry and Molecular Biology B and Immunology, School of Medicine, Murcia Biohealth Research Institute-University of Murcia (IMIB-UMU), Regional Campus of International Excellence "Campus Mare Nostrum", 30100 Murcia, Spain. Electronic address: emartin@um.es.
authors.forename: Elena
authors.initials: E
authors.lastname: Martín-Orozco
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003080:Cold Temperature; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007938:Leukemia / Q000201:enzymology* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014162:Transfection
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D047428:Protein Kinase Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Cold-stress; Collateral sensitivity; Leukemic cells; MAPK; MDR; P-glycoprotein