Rituximab-induced inhibition of YY1 and Bcl-xL expression in Ramos non-Hodgkin's lymphoma cell line via inhibition of NF-kappa B activity: role of YY1 and Bcl-xL in Fas resistance and chemoresistance, respectively.
Rituximab treatment of B non-Hodgkin's lymphoma (NHL) cell lines inhibits the constitutive NF-kappaB activity and results in the sensitization of tumor cells to both chemotherapy and Fas-induced apoptosis. Cells expressing dominant active IkappaB or treated with NF-kappaB-specific inhibitors were sensitive to both drugs and Fas agonist mAb (CH-11)-induced apoptosis. Down-regulation of Bcl-xL expression via inhibition of NF-kappaB activity correlated with chemosensitivity. The direct role of Bcl-xL in chemoresistance was demonstrated by the use of Bcl-xL-overexpressing Ramos cells, Ramos hemagglutinin (HA)-Bcl-x, which were not sensitized by rituximab to drug-induced apoptosis. However, inhibition of Bcl-xL in Ramos HA-Bcl-x resulted in sensitization to drug-induced apoptosis. The role of Bcl-xL expression in the regulation of Fas resistance was not apparent; Ramos HA-Bcl-x cells were as sensitive as the wild type to CH-11-induced apoptosis. Several lines of evidence support the direct role of the transcription repressor yin-yang 1 (YY1) in the regulation of resistance to CH-11-induced apoptosis. Inhibition of YY1 activity by either rituximab or the NO donor DETANONOate or after transfection with YY1 small interfering RNA resulted in up-regulation of Fas expression and sensitization to CH-11-induced apoptosis. These findings suggest two mechanisms underlying the chemosensitization and immunosensitization of B-NHL cells by rituximab via inhibition of NF-kappaB. The regulation of chemoresistance by NF-kappaB is mediated via Bcl-xL expression, whereas the regulation of Fas resistance by NF-kappaB is mediated via YY1 expression and activity. The potential clinical significance of these findings is discussed.
Vega
Mario I
MI
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095, USA.
Jazirehi
Ali R
AR
Huerta-Yepez
Sara
S
Bonavida
Benjamin
B
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D019008:Drug Resistance, Neoplasm / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology; D000069283:Rituximab; D013450:Sulfones / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; C416282:BAY 11-7085; D016328:NF-kappa B; D009570:Nitriles; D009603:Nitroso Compounds; D013450:Sulfones; D019014:fas Receptor; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D000069283:Rituximab