title: Characterization of the NF-?B signaling triggered by doxorubicin.
abstract: Doxorubicin (DOX) is an antibiotic used in the treatment of various cancers. However, its clinical use is limited due to the toxic effects it causes. In several biological systems reactive oxygen species (ROS) derived from DOX metabolism have been associated with its toxicity because they can alter several signal transduction pathways. One of the major signal transduction pathways activated in response to oxidant stress is that of the nuclear transcription factor ?B (NF-?B), which is crucial for cell survival, cell proliferation, and immune responses. Previous studies from our laboratory have described that DOX triggersthe activation of the MAPK (ERK, p38, and JNK) pathways, NF-?B mobilization and caspase activation in rat hepatocytes. These events were indirectly ascribed to ROS generation by pharmacological approaches. Although NF-?B mobilization is usually accompanied by up-regulation of the genes with regulatory ?B elements, our gene expression analysis rendered a quite different scenario. The aim of this work was to verify the implication of ROS in the DOX-mediated signaling and to explore the transcriptional regulatory behaviour of NF-?B mobilized by DOX. Results showed that DOX treatment induces ROS generation, particularly H2O2. DOX-induced caspase-3 activation was ROS dependent, whereas the NF-?B mobilization was a process independent of H2O2. Furthermore, DOX-mobilized NF-?B complexes were dimmers formed by p65 with all the members of the Rel family, excepting Rel B. The analysis of the NF-?B transcriptional activity performed by reporter gene assays suggests that these DOX-mobilized NF-?B complexes are not transcriptionally competent.
authors.affiliation: University of Basque Country UPV/EHU (Faculty of Medicine and Dentistry), Department of Physiology, Spain.. Electronic address: oihanala@hotmail.com.
authors.forename: Oihana
authors.initials: O
authors.lastname: Lopez de Vergara
authors.affiliation: University of Basque Country UPV/EHU (Faculty of Medicine and Dentistry), Department of Physiology, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Pablos
authors.affiliation: University of Basque Country UPV/EHU (Faculty of Medicine and Dentistry), Department of Physiology, Spain.
authors.forename: M Begoña
authors.initials: MB
authors.lastname: Ruiz-Sanz
authors.affiliation: University of Basque Country UPV/EHU (Faculty of Medicine and Dentistry), Department of Physiology, Spain.
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Ruiz-Larrea
authors.affiliation: University of Basque Country UPV/EHU (Faculty of Medicine and Dentistry), Department of Physiology, Spain.
authors.forename: Rosaura
authors.initials: R
authors.lastname: Navarro