Document Detail


The rGel/BLyS fusion toxin inhibits STAT3 signaling via down-regulation of interleukin-6 receptor in diffuse large B-cell lymphoma.
MedLine Citation:
PMID:  20654581     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Mi-Ae Lyu; Bokyung Sung; Lawrence H Cheung; John W Marks; Bharat B Aggarwal; Ricardo C T Aguiar; Michael G Rosenblum
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-07-21
Journal Detail:
Title:  Biochemical pharmacology     Volume:  80     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-09-20     Completed Date:  2010-10-06     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1335-42     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Affiliation:
Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, USA.
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MeSH Terms
Descriptor/Qualifier:
Apoptosis / 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:
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

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