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.
Marsee
Derek K
DK
Medical Scientist Program, The Ohio State University College of Medicine, Columbus 43210, USA.
Venkateswaran
Anjli
A
Tao
Haiyang
H
Vadysirisack
Douangsone
D
Zhang
Zhaoxia
Z
Vandre
Dale D
DD
Jhiang
Sissy M
SM
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