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: Melisa A Martínez-Paniagua, Stavroula Baritaki, Sara Huerta-Yepez, Vianney F Ortiz-Navarrete, Cesar González-Bonilla, Benjamin Bonavida, Mario I Vega
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 10 Issue 16 Pg. 2792-805 (Aug 15 2011) ISSN: 1551-4005 [Electronic] United States
• PMID: 21822052 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Indoles
• Myeloid Cell Leukemia Sequence 1 Protein
• NF-kappa B
• Proto-Oncogene Proteins c-bcl-2
• Pyrroles
• RNA, Small Interfering
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• TNFRSF10A protein, human
• TNFSF10 protein, human
• YY1 Transcription Factor
• YY1 protein, human
• obatoclax

Topics

• Apoptosis (drug effects)
• B-Lymphocytes (drug effects, metabolism)
• Cell Line
• Drug Resistance, Neoplasm
• Humans
• Indoles
• Myeloid Cell Leukemia Sequence 1 Protein
• NF-kappa B (antagonists & inhibitors, drug effects, metabolism)
• Proto-Oncogene Proteins c-bcl-2 (genetics, metabolism)
• Pyrroles (pharmacology)
• RNA Interference
• RNA, Small Interfering
• Receptors, TNF-Related Apoptosis-Inducing Ligand (genetics, metabolism)
• Signal Transduction (drug effects, genetics)
• TNF-Related Apoptosis-Inducing Ligand (metabolism)
• YY1 Transcription Factor (genetics, metabolism)