Abstract
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 p50cdc37 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.
Highlights
Members of the heat shock protein family function as molecular chaperones, ensuring the proper folding of newly translated proteins [1]
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, to inhibit proliferation and to increase the efficacy of radioiodide therapy in patients with thyroid cancer
We have identified hsp90 and p50cdc37 as novel proteins associated with PTC1 and demonstrated that inhibition of hsp90 function with 17-AAG reduces PTC1 protein levels
Summary
Members of the heat shock protein family function as molecular chaperones, ensuring the proper folding of newly translated proteins [1]. Hsp mediates the folding of a limited number of client proteins, including steroid hormone receptors and signaling kinases. The co-chaperone p50cdc has been shown to interact with the molecular clamp, maintaining hsp in the open state and facilitating client protein loading [10]. Hsp function can be inhibited by several members of the ansamycin family of antibiotics, including herbimycin A, geldanamycin, and 17-allylamino-17-demethoxygeldanamycin (17-AAG). Park et al [16] have demonstrated that geldanamycin decreased expression of c-Raf, inhibited thyroid cell proliferation, reduced Matrigel invasion, and induced apoptosis. All RET/PTC isoforms contain the C-terminal tyrosine kinase domain of the RET linked to the N-terminal portion of an activating gene These N-terminal proteins are expressed in thyroid follicular cells and are capable of dimerization, resulting in constitutive activation of the RET kinase domain [19]. To develop novel molecular therapies for PTC-induced thyroid cancer, we have conducted a proteomic study to identify novel PTC1-associated factors
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