Document Detail


The insulin receptor negatively regulates the action of Pseudomonas toxin-based immunotoxins and native Pseudomonas toxin.
MedLine Citation:
PMID:  23348423     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
SS1P is a recombinant immunotoxin composed of an antimesothelin Fv fragment fused to a truncated portion of Pseudomonas exotoxin A. SS1P targets and kills mesothelin-expressing tumors, which include mesothlioma as well as ovarian, lung, and pancreatic cancers. SS1P is currently in clinical trials in mesothelioma. Because insulin acting through the insulin receptor is a survival factor for many cancer cell lines, we explored how lowering insulin receptor level would affect the cytotoxic action of SS1P. We show here that siRNA knockdown of the insulin receptor enhanced the cytotoxic action of native Pseudomonas exotoxin and enhanced SS1P toxicity on several human cell lines, but did not affect the response to other cytotoxic agents such as TRAIL, etoposide, and cycloheximide. To determine how insulin receptor knockdown enhances SS1P action, we analyzed various steps involved in cell killing. We found that insulin receptor knockdown increases the cleavage of SS1P by furin, which allows more toxin to reach the cytosol and inactivate elongation factor 2. These findings indicate that the insulin receptor negatively regulates immunotoxin action.
Authors:
Xiu Fen Liu; David J FitzGerald; Ira Pastan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2013-01-24
Journal Detail:
Title:  Cancer research     Volume:  73     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-04     Completed Date:  2013-06-25     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2281-8     Citation Subset:  IM    
Copyright Information:
©2013 AACR.
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MeSH Terms
Descriptor/Qualifier:
Antibodies, Monoclonal / pharmacology*
Apoptosis
Bacterial Toxins / pharmacology*
Blotting, Western
Cell Proliferation
GPI-Linked Proteins / antagonists & inhibitors*
Humans
Immunotoxins / pharmacology*
Mesothelioma / drug therapy,  metabolism,  pathology*
Pseudomonas aeruginosa / drug effects,  genetics
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Receptor, Insulin / antagonists & inhibitors,  metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Grant Support
ID/Acronym/Agency:
ZIA BC008753-30/BC/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Bacterial Toxins; 0/GPI-Linked Proteins; 0/Immunotoxins; 0/RNA, Messenger; 0/SS1(dsFv)PE38; 0/mesothelin; EC 2.7.10.1/Receptor, Insulin
Comments/Corrections

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


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