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The Heat Shock Protein 90-Binding Geldanamycin Inhibits Cancer Cell Proliferation, Down-Regulates Oncoproteins, and Inhibits Epidermal Growth Factor-Induced Invasion in Thyroid Cancer Cell Lines

Department of Surgery, University of California, Mount Zion Medical Center (J.-W.P., M.W.Y., M.G.W., M.L., O.H.C.), San Francisco, California 94143-1674; University of California Comprehensive Cancer Center (W.C.H.), San Francisco, California 94115; and Surgical Services, Veterans Affairs Medical Center (Q.H.C.), San Francisco, California 94121

Address all correspondence and requests for reprints to: Orlo H. Clark, M.D., University of California/Mount Zion Medical Center (Surgery), 1600 Divisadero Street, San Francisco, California 94115. E-mail: clarko{at}surgery.ucsf.edu.

Heat shock protein 90 (HSP90) serves as a chaperone protein and plays a critical role in tumor cell growth and/or survival. Geldanamycin, a specific inhibitor of HSP90, is cytotoxic to several human cancer cell lines, but its effect in thyroid cancer is unknown. We, therefore, investigated the effect of geldanamycin on cell proliferation, oncoprotein expression, and invasion in human thyroid cancer cell lines. We used six thyroid cancer cell lines: TPC-1 (papillary), FTC-133, FTC-236, FTC-238 (follicular), XTC-1 (Hürthle cell), and ARO (anaplastic). We used the dimethyl-thiazol-diphenyltetrazolium bromide assay, a clonogenic assay, an apoptotic assay, and a Matrigel invasion assay. We evaluated oncoprotein expression using Western blots and flow cytometry. After 6 d of treatment with 50 nM geldanamycin, the percent inhibition of growth was 29.4% in TPC-1, 97.5% in FTC-133, 96.7% in FTC-236, 10.8% in FTC-238, 70.9% in XTC-1, and 45.5% in ARO cell lines. In the FTC-133 cell line, geldanamycin treatment decreased clonogenicity by 21% at a concentration of 50 nM; geldanamycin induced apoptosis and down-regulated c-Raf-1, mutant p53, and epidermal growth factor (EGF) receptor expression; geldanamycin inhibited EGF-stimulated invasion. In conclusion, geldanamycin inhibited cancer cell proliferation, down-regulated oncoproteins, and inhibited EGF-induced invasion in thyroid cancer cell lines.

Abbreviations: DTC, Differentiated thyroid cancer; EGF, epidermal growth factor; EGFR, EGF receptor; FCS, fetal calf serum; FITC, fluorescein isothiocyanate; FTC, follicular thyroid cancer; GRP94, glucose-regulated protein 94; HSP90, heat shock protein 90; IgG, immunoglobulin G; MTT, dimethyl-thiazol-diphenyltetrazolium bromide; PI, propidium iodide; RB, retinoblastoma gene product.

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