Rituximab-induced inhibition of YY1 and Bcl-xL expression in Ramos non-Hodgkin's lymphoma cell line via inhibition of NF-κB 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-kappa B activity and results in the sensitization of tumor cells to both chemotherapy and Fas-induced apoptosis. Cells expressing dominant active I kappa B or treated with NF-kappa B-specific inhibitors were sensitive to both drugs and Fas agonist mAb (CH-11)-induced apoptosis. Down-regulation of Bel-x(L) expression via inhibition of NF-kappa B activity correlated with chemosensitivity. The direct role of Bcl-x(L) in chemoresistance was demonstrated by the use of Bcl-x(L)-overexpressing Ramos cells, Ramos hemagglutinin (HA)-Bcl-x, which were not sensitized by rituximab to drug-induced apoptosis. However, inhibition of Bcl-x(L) in Ramos HA-Bcl-x resulted in sensitization to drug-induced apoptosis. The role of Bcl-x(L) 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 I (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-kappa B. The regulation of chemoresistance by NF-kappa B is mediated via Bcl-xL expression, whereas the regulation of Fas resistance by NF-kappa B is mediated via YY1 expression and activity. The potential clinical significance of these findings is discussed.