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Targeting Focal Adhesion Kinase with Dominant-Negative FRNK or Hsp90 Inhibitor 17-DMAG Suppresses Tumor Growth and Metastasis of SiHa Cervical Xenografts

¹ Ontario Cancer Institute, Departments of ² Laboratory Medicine and Pathobiology, ³ Medical Biophysics, and ⁴ Radiation Oncology, ⁵ Institute of Medical Sciences, and ⁶ Division of Applied Molecular Oncology, University of Toronto, Toronto, Ontario, Canada and ⁷ Division of Gynecologic Pathology, Institute of Pathology, University of Leipzig, Leipzig, Germany

Requests for reprints: David W. Hedley, Princess Margaret Hospital/Ontario Cancer Institute, 610 University Avenue, 5th Floor, Room 203, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2262; Fax: 416-946-6546; E-mail: david.hedley{at}uhn.on.ca.

Key Words: 17-DMAG • FAK • Hsp90

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. [Cancer Res 2009;69(11):4750–9]