Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 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 is a chimeric monoclonal antibody to the surface antigen CD20 and has provided better outcomes against CD20+ B-cell lymphomas than chemotherapy with conventional antitumor drugs alone. Treatment with rituximab poses a considerable problem, however, because of CD20- tumor transformation and subsequent disease progression. We have established a CD20- lymphoma cell line, RRBL1, from a diffuse large B-cell lymphoma with CD20- transformation from CD20+ follicular lymphoma after treatment with rituximab. RRBL1 was CD10+, CD19+, and CD20- by flow cytometry. CD20 expression was not detected by immunohistochemistry. Immunoblotting with whole RRBL1 cell lysate showed a very faint CD20 band only with longer exposures. The level of CD20 messenger RNA (mRNA) expression detected by quantitative reverse transcriptase-polymerase chain reaction analysis was almost 100 times lower than that in CD20+ lymphoma cells. When we treated RRBL1 cells with trichostatin A, an epigenetic drug that modulates histone-acetylation status, we detected dramatically increased CD20 mRNA and protein expression, suggesting that epigenetic mechanisms may explain the CD20- phenotype in RRBL1 cells. Thus, RRBL1 may be useful not only for analyses of mechanisms for the absence of CD20 expression in vitro but also for exploration of therapies against CD20- B-cell malignancies in vivo.
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PMID:Epigenetic regulation of CD20 protein expression in a novel B-cell lymphoma cell line, RRBL1, established from a patient treated repeatedly with rituximab-containing chemotherapy. 1767 67