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Inhibition of the Raf–MEK1/2–ERK1/2 Signaling Pathway, Bcl-_xL Down-Regulation, and Chemosensitization of Non-Hodgkin’s Lymphoma B Cells by Rituximab

Departments of ¹ Microbiology, Immunology, and Molecular Genetics and ² Medicine, Rhode Island Hospital and Brown University Medical School, Providence, Rhode Island; and ³ Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles, California

Rituximab (Rituxan, IDEC-C2B8) has been shown to sensitize non-Hodgkin’s lymphoma (NHL) cell lines to chemotherapeutic drug-induced apoptosis. Rituximab treatment of Bcl-2–deficient Ramos cells and Bcl-2–expressing Daudi cells selectively decreases Bcl-_xL expression and sensitizes the cells to paclitaxel-induced apoptosis. This study delineates the signaling pathway involved in rituximab-mediated Bcl-_xL down-regulation in Ramos and Daudi NHL B cells. We hypothesized that rituximab may interfere with the extracellular signal-regulated kinase (ERK) 1/2 pathway, leading to decreased Bcl-_xL expression. Rituximab (20 µg/mL) inhibited the kinase activity of mitogen-activated protein kinase kinase (MEK) 1/2 and reduced the phosphorylation of the components of the ERK1/2 pathway (Raf-1, MEK1/2, and ERK1/2) and decreased activator protein-1 DNA binding activity and Bcl-_xL gene expression. These events occurred with similar kinetics and were observed 3 to 6 hours after rituximab treatment. Rituximab-mediated effects were corroborated by using specific inhibitors of the ERK1/2 pathway, which also reduced Bcl-_xL levels and sensitized the NHL B cells to paclitaxel-induced apoptosis. Previous findings implicated a negative regulatory role of the Raf-1 kinase inhibitor protein (RKIP) on the ERK1/2 pathway. Rituximab treatment of NHL B cells significantly up-regulated RKIP expression, thus interrupting the ERK1/2 signaling pathway through the physical association between Raf-1 and RKIP, which was concomitant with Bcl-_xL down-regulation. These novel findings reveal a signaling pathway triggered by rituximab, whereby rituximab-mediated up-regulation of RKIP adversely regulates the activity of the ERK1/2 pathway, Bcl-_xL expression, and subsequent chemosensitization of drug-refractory NHL B cells. The significance of these findings is discussed.

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