title: Mcl-1 and YY1 inhibition and induction of DR5 by the BH3-mimetic Obatoclax (GX15-070) contribute in the sensitization of B-NHL cells to TRAIL apoptosis.
abstract: The pan Bcl-2 family antagonist Obatoclax (GX15-070), currently in clinical trials, was shown to sensitize TRAIL-resistant tumors to TRAIL-mediated apoptosis via the release of Bak and Bim from Mcl-1 or Bcl-2/Bcl-XL complexes or by the activation of Bax, though other mechanisms were not examined. Herein, we hypothesize that Obatoclax-mediated sensitization to TRAIL apoptosis may also result from alterations of the apoptotic pathways. The TRAIL-resistant B-cell line Ramos was used as a model for investigation. Treatment of Ramos cells with Obatoclax significantly inhibited the expression of several members of the Bcl-2 family, dissociated Bak from Mcl-1 and inhibited the NFκB activity. Cells treated with Mcl-1 siRNA were sensitized to TRAIL apoptosis. We examined whether the sensitization of Ramos to TRAIL by Obatoclax resulted from signaling of the DR4 and/or DR5. Transfection with DR5 siRNA, but not with DR4 siRNA, sensitized the cells to apoptosis following treatment with Obatoclax and TRAIL. The signaling via DR5 correlated with Obatoclax-induced inhibition of the DR5 repressor Yin Yang 1 (YY1). Transfection with YY1 siRNA sensitized the cells to TRAIL apoptosis following treatment with Obatoclax and TRAIL. Overall, the present findings reveal a new mechanism of Obatoclax-induced sensitization to TRAIL apoptosis and the involvement of the inhibition of NFκB activity and downstream Mcl-1 and YY1 expressions and activities.
authors.affiliation: Unidad de Investigación Biomédica, Hospital de Infectología CMN La Raza IMSS, México City, México.
authors.forename: Melisa A
authors.initials: MA
authors.lastname: Martínez-Paniagua
authors.forename: Stavroula
authors.initials: S
authors.lastname: Baritaki
authors.forename: Sara
authors.initials: S
authors.lastname: Huerta-Yepez
authors.forename: Vianney F
authors.initials: VF
authors.lastname: Ortiz-Navarrete
authors.forename: Cesar
authors.initials: C
authors.lastname: González-Bonilla
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bonavida
authors.forename: Mario I
authors.initials: MI
authors.lastname: Vega
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007211:Indoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D050986:YY1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D007211:Indoles; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; C520962:obatoclax