Document Detail


Insulin receptor substrate 1 expression enhances the sensitivity of 32D cells to chemotherapy-induced cell death.
MedLine Citation:
PMID:  22652453     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The adapters IRS1 and IRS2 link growth factor receptors to downstream signaling pathways that regulate proliferation and survival. Both suppress factor-withdrawal-induced apoptosis and have been implicated in cancer progression. However, recent studies suggest IRS1 and IRS2 mediate differential functions in cancer pathogenesis. IRS1 promoted breast cancer proliferation, while IRS2 promoted metastasis. The role of IRS1 and IRS2 in controlling cell responses to chemotherapy is unknown. To determine the role of IRS1 and IRS2 in the sensitivity of cells to chemotherapy, we treated 32D cells lacking or expressing IRS proteins with various concentrations of chemotherapeutic agents. We found that expression of IRS1, in contrast to IRS2, enhanced the sensitivity of 32D cells to chemotherapy-induced apoptosis. When IRS2 was expressed with IRS1, the cells no longer showed enhanced sensitivity. Expression of IRS1 did not alter the expression of pro- and anti-apoptotic proteins; however, 32D-IRS1 cells expressed higher levels of Annexin A2. In 32D-IRS1 cells, IRS1 and Annexin A2 were both located in cytoplasmic and membrane fractions. We also found that IRS1 coprecipitated with Annexin A2, while IRS2 did not. Decreasing Annexin A2 levels reduced 32D-IRS1 cell sensitivity to chemotherapy. These results suggest IRS1 enhances sensitivity to chemotherapy in part through Annexin A2.
Authors:
Holly A Porter; Gregory B Carey; Achsah D Keegan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-28
Journal Detail:
Title:  Experimental cell research     Volume:  318     ISSN:  1090-2422     ISO Abbreviation:  Exp. Cell Res.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-07-03     Completed Date:  2012-09-14     Revised Date:  2014-04-08    
Medline Journal Info:
Nlm Unique ID:  0373226     Medline TA:  Exp Cell Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1745-58     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Animals
Annexin A2 / metabolism
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Cell Death / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Insulin Receptor Substrate Proteins / biosynthesis*,  metabolism
Mice
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
1F31CA142165-01A1/CA/NCI NIH HHS; F31 CA142165/CA/NCI NIH HHS; K22CA128882/CA/NCI NIH HHS; R01 AI038985/AI/NIAID NIH HHS; R01AI038985-12-17/AI/NIAID NIH HHS; R25-GM55036/GM/NIGMS NIH HHS; T32 HL007698/HL/NHLBI NIH HHS; T32HL007698/HL/NHLBI NIH HHS; UH2CA158689/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Annexin A2; 0/Insulin Receptor Substrate Proteins; 0/Irs1 protein, mouse
Comments/Corrections

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