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B Activity: Role of YY1 and Bcl-xL in Fas Resistance and Chemoresistance, Respectively1
* Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA 90095; and
Unidad de Investigación Médica en Inmunología e Infectología, Hospital de Infectología, Centro Medico Nacional La Raza, Instituto Mexicano del Seguro Social, Mexico City, Mexico
Rituximab treatment of B non-Hodgkin’s lymphoma (NHL) cell lines inhibits the constitutive NF-
B activity and results in the sensitization of tumor cells to both chemotherapy and Fas-induced apoptosis. Cells expressing dominant active IB or treated with NF-B-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-B 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-B. The regulation of chemoresistance by NF-B is mediated via Bcl-xL expression, whereas the regulation of Fas resistance by NF-B is mediated via YY1 expression and activity. The potential clinical significance of these findings is discussed.
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