title: KT5823 differentially modulates sodium iodide symporter expression, activity, and glycosylation between thyroid and breast cancer cells.
abstract: Na(+)/I(-) symporter (NIS)-mediated iodide uptake into thyroid follicular cells serves as the basis of radioiodine therapy for thyroid cancer. NIS protein is also expressed in the majority of breast tumors, raising potential for radionuclide therapy of breast cancer. KT5823, a staurosporine-related protein kinase inhibitor, has been shown to increase thyroid-stimulating hormone-induced NIS expression, and thus iodide uptake, in thyroid cells. In this study, we found that KT5823 does not increase but decreases iodide uptake within 0.5 h of treatment in trans-retinoic acid and hydrocortisone-treated MCF-7 breast cancer cells. Moreover, KT5823 accumulates hypoglycosylated NIS, and this effect is much more evident in breast cancer cells than thyroid cells. The hypoglycosylated NIS is core glycosylated, has not been processed through the Golgi apparatus, but is capable of trafficking to the cell surface. KT5823 impedes complex NIS glycosylation at a regulatory point similar to brefeldin A along the N-linked glycosylation pathway, rather than targeting a specific N-glycosylated site of NIS. KT5823-mediated effects on NIS activity and glycosylation are also observed in other breast cancer cells as well as human embryonic kidney cells expressing exogenous NIS. Taken together, KT5823 will serve as a valuable pharmacological reagent to uncover mechanisms underlying differential NIS regulation between thyroid and breast cancer cells at multiple levels.
authors.affiliation: Integrated Biomedical Sciences Graduate Program, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Sasha
authors.initials: S
authors.lastname: Beyer
authors.forename: Aparna
authors.initials: A
authors.lastname: Lakshmanan
authors.forename: Yu-Yu
authors.initials: YY
authors.lastname: Liu
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: Irene
authors.initials: I
authors.lastname: Wapnir
authors.forename: Albert
authors.initials: A
authors.lastname: Smolenski
authors.forename: Sissy
authors.initials: S
authors.lastname: Jhiang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D020126:Brefeldin A / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology*; D002460:Cell Line; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006031:Glycosylation; D006801:Humans; D006854:Hydrocortisone; D007454:Iodides / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D027981:Symporters / Q000378:metabolism*; D013961:Thyroid Gland / Q000166:cytology*; D013972:Thyrotropin; D014212:Tretinoin; D000099209:Sodium-Iodide Symporters
chemical_list: D020126:Brefeldin A; D002227:Carbazoles; D006854:Hydrocortisone; D007454:Iodides; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D027981:Symporters; D013972:Thyrotropin; D014212:Tretinoin; D000099209:Sodium-Iodide Symporters; C073601:KT 5823