Document Detail


Targeting focal adhesion kinase with dominant-negative FRNK or Hsp90 inhibitor 17-DMAG suppresses tumor growth and metastasis of SiHa cervical xenografts.
MedLine Citation:
PMID:  19458065     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Focal adhesion kinase (FAK), a nonreceptor protein tyrosine kinase and key modulator of integrin signaling, is widely expressed in different tissues and cell types. Recent evidence indicates a central function of FAK in neoplasia where the kinase contributes to cell proliferation, resistance to apoptosis and anoikis, invasiveness, and metastasis. FAK, like other signaling kinases, is dependent on the chaperone heat shock protein 90 (Hsp90) for its stability and proper function. Thus, inhibition of Hsp90 might be a way of disrupting FAK signaling and, consequently, tumor progression. FAK is expressed in high-grade squamous intraepithelial lesions and metastatic cervical carcinomas but not in nonneoplastic cervical mucosa. In SiHa, a cervical cancer cell line with characteristics of epithelial-to-mesenchymal transition, the stable expression of dominant-negative FAK-related nonkinase decreases anchorage independence and delays xenograft growth. FAK-related nonkinase as well as the Hsp90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin both negatively interfere with FAK signaling and focal adhesion turnover. Short-term 17-dimethylaminoethylamino-17-demethoxygeldanamycin treatment prolongs survival in a SiHa lung metastasis model and chronic administration suppresses tumor growth as well as metastatic spread in orthotopic xenografts. Taken together, our data suggest that FAK is of importance for tumor progression in cervical cancer and that disruption of FAK signaling by Hsp90 inhibition might be an avenue to restrain tumor growth as well as metastatic spread.
Authors:
Joerg Schwock; Neesha Dhani; Mary Ping-Jiang Cao; Jinzi Zheng; Richard Clarkson; Nikolina Radulovich; Roya Navab; Lars-Christian Horn; David W Hedley
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-05-19
Journal Detail:
Title:  Cancer research     Volume:  69     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-06-02     Completed Date:  2009-07-15     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4750-9     Citation Subset:  IM    
Affiliation:
Ontario Cancer Institute, Departments of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / therapeutic use
Benzoquinones / administration & dosage,  therapeutic use*
Carcinoma, Squamous Cell / drug therapy*,  genetics,  pathology
Cell Line, Tumor
Cell Proliferation / drug effects*
Disease Progression
Drug Delivery Systems / methods
Female
Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*,  genetics
Gene Targeting
Genes, Dominant / physiology
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
Humans
Lactams, Macrocyclic / administration & dosage,  therapeutic use*
Mice
Mice, SCID
Neoplasm Metastasis
Protein-Tyrosine Kinases / administration & dosage,  genetics,  therapeutic use*
Tumor Burden / drug effects
Uterine Cervical Neoplasms / drug therapy*,  genetics,  pathology
Xenograft Model Antitumor Assays
Chemical
Reg. No./Substance:
0/17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; 0/Antineoplastic Agents; 0/Benzoquinones; 0/HSP90 Heat-Shock Proteins; 0/Lactams, Macrocyclic; EC 2.7.1.-/FAK-related nonkinase; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.2/Focal Adhesion Protein-Tyrosine Kinases

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


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