Document Detail

Hsp90 stabilizes Cdc25A and counteracts heat shock-mediated Cdc25A degradation and cell-cycle attenuation in pancreatic carcinoma cells.
MedLine Citation:
PMID:  22843495     Owner:  NLM     Status:  MEDLINE    
Pancreas cancer cells escape most treatment options. Heat shock protein (Hsp)90 is frequently over-expressed in pancreas carcinomas and protects a number of cell-cycle regulators such as the proto-oncogene Cdc25A. We show that inhibition of Hsp90 with geldanamycin (GD) destabilizes Cdc25A independent of Chk1/2, whereas the standard drug for pancreas carcinoma treatment, gemcitabine (GEM), causes Cdc25A degradation through the activation of Chk2. Both agents applied together additively inhibit the expression of Cdc25A and the proliferation of pancreas carcinoma cells thereby demonstrating that both Cdc25A-destabilizing/degrading pathways are separated. The role of Hsp90 as stabilizer of Cdc25A in pancreas carcinoma cells is further supported by two novel synthetic inhibitors 4-tosylcyclonovobiocic acid and 7-tosylcyclonovobiocic acid and specific Hsp90AB1 (Hsp90β) shRNA. Our data show that targeting Hsp90 reduced the resistance of pancreas carcinoma cells to treatment with GEM.
Benedikt Giessrigl; Sigurd Krieger; Margit Rosner; Nicole Huttary; Philipp Saiko; Mouad Alami; Samir Messaoudi; Jean-François Peyrat; Alexandre Maciuk; Michaela Gollinger; Sabine Kopf; Egidijus Kazlauskas; Peter Mazal; Thomas Szekeres; Markus Hengstschläger; Daumantas Matulis; Walter Jäger; Georg Krupitza
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-07-25
Journal Detail:
Title:  Human molecular genetics     Volume:  21     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-16     Completed Date:  2013-04-03     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  4615-27     Citation Subset:  IM    
1Institute of Clinical Pathology, Medical University of Vienna, General Hospital of Vienna, Waehringer Guertel 18-20, Vienna A-1090, Austria.
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MeSH Terms
Benzoquinones / pharmacology
Cell Cycle Proteins* / drug effects,  metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Deoxycytidine / analogs & derivatives,  pharmacology
Gene Expression Regulation, Neoplastic / drug effects*
HSP90 Heat-Shock Proteins* / antagonists & inhibitors,  metabolism
Lactams, Macrocyclic / pharmacology
Novobiocin / analogs & derivatives,  pharmacology
Pancreatic Neoplasms* / genetics,  metabolism
Protein Kinases / metabolism
Protein-Serine-Threonine Kinases / metabolism
Proteolysis / drug effects
cdc25 Phosphatases* / genetics,  metabolism
Reg. No./Substance:
0/4-tosylcyclonovobiocic acid; 0/7-tosylcyclonovobiocic acid; 0/Benzoquinones; 0/Cell Cycle Proteins; 0/HSP90 Heat-Shock Proteins; 0/Lactams, Macrocyclic; 303-81-1/Novobiocin; 951-77-9/Deoxycytidine; B76N6SBZ8R/gemcitabine; EC 2.7.-/Protein Kinases; EC kinase 2; EC kinase 1; EC Kinases; EC protein, human; EC Phosphatases; Z3K3VJ16KU/geldanamycin

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