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J. Biol. Chem., Vol. 279, Issue 42, 43990-43997, October 15, 2004

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Inhibition of Heat Shock Protein 90, a Novel RET/PTC1-associated Protein, Increases Radioiodide Accumulation in Thyroid Cells^*

Derek K. Marsee¶, Anjli Venkateswaran¶||, Haiyang Tao¶, Douangsone Vadysirisack¶**, Zhaoxia Zhang¶||, Dale D. Vandre¶, and Sissy M. Jhiang¶

From the Medical Scientist Program, ^**Integrated Biomedical Science Graduate Program, ^||Biochemistry Program, and Departments of ^¶Physiology and Cell Biology and Internal Medicine, The Ohio State University College of Medicine, Columbus, Ohio 43210

RET/PTC1 is a rearranged form of the RET tyrosine kinase commonly seen in papillary thyroid carcinomas. It has been shown that RET/PTC1 decreases expression of the sodium/iodide symporter (NIS), the molecule that mediates radioiodide therapy for thyroid cancer. Using proteomic analysis, we identify hsp90 and its co-chaperone p50^cdc37 as novel proteins associated with RET/PTC1. Inhibition of hsp90 function with 17-allylamino-17-demothoxygeldanamycin (17-AAG) reduces RET/PTC1 protein levels. Furthermore, 17-AAG increases radioiodide accumulation in thyroid cells, mediated in part through a protein kinase A-independent mechanism. We show that 17-AAG does not increase the total amount of NIS protein or cell surface NIS localization. Instead, 17-AAG increases radioiodide accumulation by decreasing iodide efflux. Finally, the ability of 17-AAG to increase radioiodide accumulation is not restricted to thyroid cells expressing RET/PTC1. These findings suggest that 17-AAG may be useful as a chemotherapeutic agent, not only to inhibit proliferation but also to increase the efficacy of radioiodide therapy in patients with thyroid cancer.

Received for publication, July 6, 2004 , and in revised form, August 6, 2004.

^* This work was supported in part by National Institutes of Health (NIH) Grant R01CA60074 (to S. M. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by NIH Grant T32DE14320.

To whom correspondence should be addressed: The Ohio State University, 304 Hamilton Hall, Columbus, OH 43210. Tel.: 614-292-4312; Fax: 614-292-4888; E-mail: jhiang.1{at}osu.edu.

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