| The rGel/BLyS fusion toxin inhibits STAT3 signaling via down-regulation of interleukin-6 receptor in diffuse large B-cell lymphoma. | |
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MedLine Citation:
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PMID: 20654581 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Aberrant signal transducer and activator of transcription (STAT)3 signaling participates in the development and progress of human cancers. We previously generated a highly cytotoxic fusion toxin designated rGel/BLyS for receptor-mediated delivery of the rGel toxin to malignant B-cells. In this study, we examined this fusion toxin for its ability to impact STAT3 signaling in diffuse large B-cell lymphoma (DLBCL). The activated B cell-like DLBCL lines were found to express higher levels of interleukin-6 receptor (IL-6R) and STAT3 than did the germinal center B cell-like DLBCL lines. Treatment of DLBCL cells with rGel/BLyS resulted in down-regulation of IL-6R and inhibited STAT3 phosphorylation, STAT3-DNA binding activity, and IL-6-inducible STAT3 reporter gene activity. In agreement with these results, we additionally found that rGel/BLyS down-regulated levels of several STAT3 targets (c-Myc, p21, Mcl-1, and Bcl-x(L)) and p-SYK, a positive regulator of STAT3. Inhibition of IL-6R-mediated STAT3 signaling by rGel/BLyS led to growth inhibition, triggered accumulation of cells in the sub-G(1) phase of the cell cycle, and induced apoptosis. Our results indicate that rGel/BLyS is an excellent candidate for the treatment of aggressive DLBCL which is resistant to conventional chemotherapeutic regimens and STAT3 signaling pathway may be an attractive therapeutic target for non-Hodgkin's lymphoma. |
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Authors:
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Mi-Ae Lyu; Bokyung Sung; Lawrence H Cheung; John W Marks; Bharat B Aggarwal; Ricardo C T Aguiar; Michael G Rosenblum |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-07-21 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 80 ISSN: 1873-2968 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-09-20 Completed Date: 2010-10-06 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1335-42 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Apoptosis
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drug effects B-Cell Activating Factor / pharmacology* Cell Line, Tumor DNA / metabolism Down-Regulation G1 Phase / drug effects Humans Intracellular Signaling Peptides and Proteins / metabolism Lymphoma, Large B-Cell, Diffuse / drug therapy*, metabolism, pathology Phosphorylation Protein-Tyrosine Kinases / metabolism Proto-Oncogene Proteins c-akt / metabolism Receptors, Interleukin-6 / antagonists & inhibitors* Recombinant Fusion Proteins / pharmacology* Ribosome Inactivating Proteins, Type 1 / pharmacology* STAT3 Transcription Factor / antagonists & inhibitors*, metabolism Signal Transduction / drug effects* |
| Chemical | |
Reg. No./Substance:
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0/B-Cell Activating Factor; 0/Intracellular Signaling Peptides and Proteins; 0/Receptors, Interleukin-6; 0/Recombinant Fusion Proteins; 0/Ribosome Inactivating Proteins, Type 1; 0/STAT3 Transcription Factor; 0/STAT3 protein, human; 75037-46-6/GEL protein, Gelonium multiflorum; 9007-49-2/DNA; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.1/Syk kinase; EC 2.7.11.1/Proto-Oncogene Proteins c-akt |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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