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Martinez-Paniagua M.A.,Hospital Of Infectologia Cmn La Raza Imss | Martinez-Paniagua M.A.,National Autonomous University of Mexico | Martinez-Paniagua M.A.,Jonnson Comprehensive Cancer Center at | Baritaki S.,Jonnson Comprehensive Cancer Center at | And 7 more authors.
Cell Cycle | Year: 2011

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. © 2011 Landes Bioscience.


Vega M.I.,Jonnson Comprehensive Cancer Center at | Vega M.I.,Hospital Of Infectologia | Baritaki S.,Jonnson Comprehensive Cancer Center at | Huerta-Yepez S.,Jonnson Comprehensive Cancer Center at | And 4 more authors.
Leukemia and Lymphoma | Year: 2011

Rituximab (anti-CD20 mAb) mediates antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis in B-NHL cells. The contribution of other host-mediated cytotoxic effects has not been examined. The expression of death-inducing ligands (e.g. TRAIL) by host effector cells may contribute to the mechanism of tumor cell destruction in vivo by rituximab-mediated sensitization of resistant B-cell non-Hodgkin lymphoma (B-NHL) cells. We have examined the sensitizing activity of rituximab on B-NHL cell lines resistant to TRAIL (as model) and natural killer (NK)-induced apoptosis. Treatment of TRAIL-resistant B-NHL cell lines with rituximab sensitized the cells to TRAIL apoptosis and synergy was achieved via activation of the type II mitochondrial pathway for apoptosis. Further, rituximab (Fab′)2-treated tumor cells were killed by purified peripheral blood-derived NK cells via TRAIL. Treatment of B-NHL cells with rituximab inhibited both YY1 DNA-binding activity and expression. Rituximab-mediated sensitization to TRAIL apoptosis was due, in large part, to rituximab-mediated inhibition of the transcription factor Yin Yang 1 (YY1). The direct role of YY1 in TRAIL sensitization by rituximab was shown in cells transfected with YY1 siRNA, and such cells mimicked rituximab and became sensitive to TRAIL-induced apoptosis. These data suggest that, in vivo, host effector cells expressing TRAIL may contribute to rituximab-mediated depletion of B-NHL cells. © 2011 Informa UK, Ltd.

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