Inhibition of heat shock protein 90, a novel RET/PTC1-associated protein, increases radioiodide accumulation in thyroid cells.
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.
Medical Scientist Program, The Ohio State University College of Medicine, Columbus 43210, USA.
Derek K
DK
Marsee
Anjli
A
Venkateswaran
Haiyang
H
Tao
Douangsone
D
Vadysirisack
Zhaoxia
Z
Zhang
Dale D
DD
Vandre
Sissy M
SM
Jhiang
D000818:Animals; D016227:Benzoquinones; D002460:Cell Line; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D047908:Intracellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics*; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011506:Proteins / Q000037:antagonists & inhibitors*; D011877:Radionuclide Imaging; D051381:Rats; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology; D027981:Symporters / Q000378:metabolism / Q000528:radiation effects; D013961:Thyroid Gland / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism; D014162:Transfection; D000099209:Sodium-Iodide Symporters
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins; D015513:Oncogene Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011506:Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D017828:Rifabutin; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C000606239:Ptch1 protein, rat; C112765:tanespimycin