Document Detail


Expression and effects of inhibition of type I insulin-like growth factor receptor tyrosine kinase in mantle cell lymphoma.
MedLine Citation:
PMID:  21330319     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Type I insulin-like growth factor receptor (IGF-IR) tyrosine kinase induces significant oncogenic effects. Strategies to block IGF-IR signaling are being tested in clinical trials that include patients with aggressive solid malignancies. Mantle cell lymphoma is a B-cell neoplasm with poor prognosis and a tendency to develop resistance. The expression and potential significance of IGF-IR in mantle cell lymphoma are not known.
DESIGN AND METHODS: We used reverse transcriptase polymerase chain reaction, quantitative real-time polymerase chain reaction, immunoprecipitation, western blotting, flow cytometry, and immunohistochemistry to analyze the expression of IGF-IR mRNA, and IGF-IR and pIGF-IR proteins in mantle cell lymphoma cell lines and patients' specimens. Selective and specific blockade of IGF-IR was achieved using picropodophyllin and short-interfering RNA, respectively. Cell viability, apoptosis, cell cycle, cellular morphology, cell proliferation, and target proteins were then analyzed.
RESULTS: We detected the expression of IGF-IR and pIGF-IR in mantle cell lymphoma cell lines. Notably, IGF-IR molecules/cell were markedly increased in mantle cell lymphoma cell lines compared with human B-lymphocytes. IGF-IR and pIGF-IR were also detected in 78% and 74%, respectively, of 23 primary mantle cell lymphoma specimens. Treatment of serum-deprived mantle cell lymphoma cell lines with IGF-I salvaged these cells from apoptosis. Selective inhibition of IGF-IR by picropodophyllin decreased the viability and proliferation of mantle cell lymphoma cell lines, and induced apoptosis and cell cycle arrest. Selective inhibition of IGF-IR was associated with caspase-3, caspase-8, caspase-9, and PARP cleavage, cytochrome c release, up-regulation of cyclin B1, and down-regulation of cyclin D1, pCdc2, pIRS-1, pAkt, and pJnk. Similar results were obtained by using IGF-IR short-interfering RNA. In addition, picropodophyllin decreased the viability and proliferation of primary mantle cell lymphoma cells that expressed IGF-IR.
CONCLUSIONS: IGF-IR is up-regulated and frequently activated in mantle cell lymphoma. Our data suggest that IGF-IR could be a molecular target for the treatment of mantle cell lymphoma.
Authors:
Deeksha Vishwamitra; Ping Shi; Desiree Wilson; Roxsan Manshouri; Francisco Vega; Ellen J Schlette; Hesham M Amin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-02-17
Journal Detail:
Title:  Haematologica     Volume:  96     ISSN:  1592-8721     ISO Abbreviation:  Haematologica     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-02     Completed Date:  2011-09-21     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  0417435     Medline TA:  Haematologica     Country:  Italy    
Other Details:
Languages:  eng     Pagination:  871-80     Citation Subset:  IM    
Affiliation:
Department of Hematopathology, Unit 72, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
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MeSH Terms
Descriptor/Qualifier:
Aged
Aged, 80 and over
Apoptosis / drug effects,  genetics
Cell Line, Tumor
Down-Regulation / drug effects
Female
Gene Expression Regulation, Neoplastic* / drug effects
Humans
Insulin-Like Growth Factor I / genetics
K562 Cells
Lymphoma, Mantle-Cell / enzymology*
Male
Middle Aged
Podophyllotoxin / analogs & derivatives,  pharmacology
Protein Kinase Inhibitors / pharmacology
Protein-Tyrosine Kinases / antagonists & inhibitors*,  genetics,  metabolism*
RNA, Messenger / metabolism
Receptor, IGF Type 1 / antagonists & inhibitors,  genetics,  metabolism*
Signal Transduction / drug effects
Grant Support
ID/Acronym/Agency:
CA114395/CA/NCI NIH HHS; T34GM079088/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Protein Kinase Inhibitors; 0/RNA, Messenger; 0F35AOI227/picropodophyllin; 518-28-5/Podophyllotoxin; 67763-96-6/Insulin-Like Growth Factor I; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.1/Receptor, IGF Type 1
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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