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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.
Cancer Res. 2004 Oct 01; 64(19):7117-26.CR

Abstract

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 microg/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.

Authors+Show Affiliations

Department of Microbiology, Immunology, and Molecular Genetics, Rhode Island Hospital and Brown University Medical School, Providence, Rhode Island, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

15466208

Citation

Jazirehi, Ali R., et al. "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." Cancer Research, vol. 64, no. 19, 2004, pp. 7117-26.
Jazirehi AR, Vega MI, Chatterjee D, et al. 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. Cancer Res. 2004;64(19):7117-26.
Jazirehi, A. R., Vega, M. I., Chatterjee, D., Goodglick, L., & Bonavida, B. (2004). 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. Cancer Research, 64(19), 7117-26.
Jazirehi AR, et al. 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. Cancer Res. 2004 Oct 1;64(19):7117-26. PubMed PMID: 15466208.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Jazirehi,Ali R, AU - Vega,Mario I, AU - Chatterjee,Devasis, AU - Goodglick,Lee, AU - Bonavida,Benjamin, PY - 2004/10/7/pubmed PY - 2004/11/17/medline PY - 2004/10/7/entrez SP - 7117 EP - 26 JF - Cancer research JO - Cancer Res. VL - 64 IS - 19 N2 - 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 microg/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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/15466208/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_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15466208 DB - PRIME DP - Unbound Medicine ER -