Document Detail


RNA interference demonstrates a novel role for integrin-linked kinase as a determinant of pancreatic adenocarcinoma cell gemcitabine chemoresistance.
MedLine Citation:
PMID:  15867245     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Integrin-linked kinase (ILK) facilitates signal transduction between extracellular events and important intracellular survival pathways involving protein kinase B/Akt. We examined the role of ILK in determining pancreatic adenocarcinoma cellular chemoresistance to the nucleoside analogue gemcitabine. Cellular ILK expression was quantified by Western blot analysis. We examined the effects of overexpression of active ILK and of ILK knockdown induced by RNA interference on gemcitabine chemoresistance. We also examined the effects of modulating ILK expression on gemcitabine-induced caspase 3-mediated apoptosis, phosphorylation status of Akt (Ser473) and glycogen synthase kinase. Overexpression of ILK increased cellular gemcitabine chemoresistance, whereas ILK knockdown induced chemosensitization via increased caspase 3-mediated apoptosis. ILK knockdown attenuated Akt Ser473 and glycogen synthase kinase phosphorylation, whereas overexpression of constitutively active myristoylated Akt was sufficient to induce significant recovery in gemcitabine chemoresistance in the presence of ILK knockdown. Levels of ILK expression affect gemcitabine chemoresistance in pancreatic adenocarcinoma cells. This novel finding suggests that therapies directed against ILK and its downstream signaling targets may have the potential to enhance the efficacy of gemcitabine-based chemotherapy.
Authors:
Mark S Duxbury; Hiromichi Ito; Eric Benoit; Talat Waseem; Stanley W Ashley; Edward E Whang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  11     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2005 May 
Date Detail:
Created Date:  2005-05-03     Completed Date:  2005-08-01     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3433-8     Citation Subset:  IM    
Affiliation:
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / drug therapy,  enzymology,  pathology
Antimetabolites, Antineoplastic / pharmacology
Apoptosis / drug effects
Blotting, Western
Caspases / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Deoxycytidine / analogs & derivatives*,  pharmacology*
Drug Resistance, Neoplasm
Glycogen Synthase Kinases / metabolism
Humans
Inhibitory Concentration 50
Pancreatic Neoplasms / drug therapy,  enzymology,  pathology
Phosphorylation
Protein-Serine-Threonine Kinases / genetics,  metabolism*,  physiology
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-akt
RNA Interference*
RNA, Small Interfering / genetics,  metabolism
Serine / metabolism
Transfection
Grant Support
ID/Acronym/Agency:
R01 CA114103-01/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antimetabolites, Antineoplastic; 0/Proto-Oncogene Proteins; 0/RNA, Small Interfering; 56-45-1/Serine; 951-77-9/Deoxycytidine; B76N6SBZ8R/gemcitabine; EC 2.7.1.-/integrin-linked kinase; EC 2.7.11.-/Glycogen Synthase Kinases; EC 2.7.11.1/AKT1 protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.4.22.-/Caspases
Comments/Corrections

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