| RNA interference demonstrates a novel role for integrin-linked kinase as a determinant of pancreatic adenocarcinoma cell gemcitabine chemoresistance. | |
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MedLine Citation:
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PMID: 15867245 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Mark S Duxbury; Hiromichi Ito; Eric Benoit; Talat Waseem; Stanley W Ashley; Edward E Whang |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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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:
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Created Date: 2005-05-03 Completed Date: 2005-08-01 Revised Date: 2012-06-22 |
Medline Journal Info:
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Nlm Unique ID: 9502500 Medline TA: Clin Cancer Res Country: United States |
Other Details:
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Languages: eng Pagination: 3433-8 Citation Subset: IM |
Affiliation:
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Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenocarcinoma
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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:
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R01 CA114103-01/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antimetabolites, Antineoplastic; 0/Proto-Oncogene Proteins; 0/RNA, Small Interfering; 103882-84-4/gemcitabine; 56-45-1/Serine; 951-77-9/Deoxycytidine; 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 | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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