A potential mechanism of rituximab-induced inhibition of tumor growth through its sensitization to tumor necrosis factor-related apoptosis-inducing ligand-expressing host cytotoxic cells.
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.
Department of Microbiology, Jonnson Comprehensive Cancer Center at UCLA, Los Angeles, CA, USA.
Mario I
MI
Vega
Stavroula
S
Baritaki
Sara
S
Huerta-Yepez
Melisa A
MA
Martinez-Paniagua
Benjamin
B
Bonavida
D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D016393:Lymphoma, B-Cell / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D000069283:Rituximab; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D050986:YY1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D058846:Antibodies, Monoclonal, Murine-Derived; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D050986:YY1 Transcription Factor; C494698:YY1 protein, human; D000069283:Rituximab