Cell cycle (Georgetown, Tex.), 2011-08, Vol.10 (16), p.2792-2805
2011
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- Autor(en) / Beteiligte
- Titel
- 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
- Ist Teil von
- Cell cycle (Georgetown, Tex.), 2011-08, Vol.10 (16), p.2792-2805
- Ort / Verlag
- United States: Taylor & Francis
- Erscheinungsjahr
- 2011
- Quelle
- Taylor & Francis Journals Auto-Holdings Collection
- Beschreibungen/Notizen
- 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-X L 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1538-4101eISSN: 1551-4005DOI: 10.4161/cc.10.16.16952Titel-ID: cdi_crossref_primary_10_4161_cc_10_16_16952
- Format
- –
- Schlagworte
- Apoptosis - drug effects, B-Lymphocytes - drug effects, B-Lymphocytes - metabolism, Binding, Biology, Bioscience, Calcium, Cancer, Cell, Cell Line, Cycle, Drug Resistance, Neoplasm, Humans, Landes, Myeloid Cell Leukemia Sequence 1 Protein, NF-kappa B - antagonists & inhibitors, NF-kappa B - drug effects, NF-kappa B - metabolism, Organogenesis, Proteins, Proto-Oncogene Proteins c-bcl-2 - genetics, Proto-Oncogene Proteins c-bcl-2 - metabolism, Pyrroles - pharmacology, Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics, Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism, RNA Interference, RNA, Small Interfering, Signal Transduction - drug effects, Signal Transduction - genetics, TNF-Related Apoptosis-Inducing Ligand - metabolism, YY1 Transcription Factor - genetics, YY1 Transcription Factor - metabolism