Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rituximab (chimeric anti-CD20 monoclonal antibodies) is currently being used in the treatment of B non-Hodgkin's lymphoma (NHL). We have recently reported that rituximab triggers and modifies various intracellular signaling pathways in NHL B-cell lines, resulting in reverting the chemoresistant phenotype to a sensitive phenotype. This study investigated whether rituximab also modifies intracellular signaling pathways resulting in the sensitization of NHL cells to Fas-induced apoptosis. Treatment of the Fas-resistant NHL cell lines (2F7, Ramos and Raji) with rituximab sensitized the cells to CH-11 (FasL agonist mAb)-induced apoptosis and synergy was achieved. Fas expression was upregulated by rituximab as early as 6 h post-treatment as determined by flow cytometry, reverse transcriptase-polymerase chain reaction and Western blot. Rituximab inhibited both the expression and activity of the transcription repressor Yin-Yang 1 (YY1) that negatively regulates Fas transcription. Inhibition of YY1 resulted in the upregulation of Fas expression and sensitization of the tumor cells to CH-11-induced apoptosis. The downregulation of YY1 expression was the result of rituximab-induced inhibition of both the p38 mitogen-activated protein kinase (MAPK) signaling pathway and constitutive nuclear factor kappa of B cells (NF-kappaB) activity. The involvement of NF-kappaB and YY1 in the regulation of Fas expression was corroborated by the use of Ramos cells with a dominant-active inhibitor of NF-kappaB (Ramos IkappaB-estrogen receptor (ER) mutant) and by silencing YY1 with YY1 siRNA, respectively. Further, the role of rituximab-mediated inhibition of the p38 MAPK/NF-kappaB/YY1 pathway in the regulation of Fas and sensitization to CH-11-induced apoptosis was validated by the use of specific chemical inhibitors of this pathway and which mimicked rituximab-mediated effects. These findings provide a novel mechanism of rituximab-mediated activity by sensitizing NHL cells to Fas-induced apoptosis.
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PMID:Rituximab (chimeric anti-CD20) sensitizes B-NHL cell lines to Fas-induced apoptosis. 1610 77

Rituximab (chimeric anti-CD20 monoclonal antibody) is the first Food and Drug Administration approved antitumor antibody and is used in the treatment of B-non-Hodgkin's lymphoma (B-NHL). It is used as single monotherapy or in combination with chemotherapy and has improved the treatment outcome of patients with B-NHL. The in vivo mechanisms of rituximab-mediated antitumor effects include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cell cytotoxicity (CDC), growth-inhibition and apoptosis. A subset of patients does not initially respond to rituximab and several responsive patients develop resistance to further rituximab treatment. The mechanism of rituximab unresponsiveness is not known. Besides the above-postulated mechanisms, rituximab has been shown to trigger the cells via CD-20. Studies performed with B-NHL cell lines as model systems revealed several novel mechanisms of rituximab-mediated effects that are involved in chemo/immunosensitization and the development of resistance to rituximab. Rituximab has been shown to inhibit the p38 mitogen-activated protein kinase, nuclear factor-kappaB (NF-kappaB), extracellular signal-regulated kinase 1/2 (ERK 1/2) and AKT antiapoptotic survival pathways, all of which result in upregulation of phosphatase and tensin homolog deleted on chromosome ten and Raf kinase inhibitor protein and in the downregulation of antiapoptotic gene products (particularly Bcl-2, Bcl-(xL) and Mcl-1), and resulting in chemo/immunosensitization. Further, rituximab treatment inhibits the overexpressed transcription repressor Yin Yang 1 (YY1), which negatively regulates Fas and DR5 expression and its inhibition leads to sensitization to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Rituximab-resistant clones were generated as model to examine the mechanism of in vivo rituximab unresponsiveness. These clones showed reduced expression of CD20 and hyperactivation of the above antiapoptotic signaling pathways and failure of rituximab to trigger the cells leading to inhibition of ADCC, CDC and chemo/immunosensitization. Interference with the hyperactivated pathways with various pharmacological and proteasome inhibitors reversed resistance. Furthermore, the above findings have identified several gene products that can serve as new prognostic/diagnostic biomarkers as well as targets for therapeutic intervention in B-NHL.
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PMID:Rituximab-induced inhibition of antiapoptotic cell survival pathways: implications in chemo/immunoresistance, rituximab unresponsiveness, prognostic and novel therapeutic interventions. 1753 16