Sunitinib Inhibits MEK/ERK and SAPK/JNK Pathways and Increases Sodium/Iodide Symporter Expression in Papillary Thyroid Cancer

• DOI: 10.1089/thy.2010.0008
• Publication Date: 2010-07-14T22:47:43Z
• Authors: Mike S. Fenton; Kenneth M. Marion; Andrew K. Salem; Rachel Hogen; Faramarz Naeim; Jerome M. Hershman
• Keywords: 0301 basic medicine; Indoles; Symporters; MAP Kinase Kinase 4; Antineoplastic Agents; Carcinoma, Papillary; 3. Good health; 03 medical and health sciences; Cell Line, Tumor; Sunitinib; Humans; Pyrroles; Thyroid Neoplasms; Extracellular Signal-Regulated MAP Kinases; Protein Kinase Inhibitors; Cell Proliferation; Signal Transduction

Sunitinib malate (Sutent, Pfizer, Inc.; SU11248) is a selective, multitargeted inhibitor of receptor tyrosine kinases and has been shown to inhibit receptors for VEGF, PDGF, KIT, FLT3, RET. The objective this study was determine the effects sunitinib on signal transduction pathways gene expression iodide-metabolizing proteins in papillary cancer cells with RET/PTC1 rearrangement.We investigated cell growth, pathways, thyroid-specific thyroid (PTC) lines that had rearrangement.Sunitinib inhibited proliferation subclones time- dose-related manner. mean 50% lethal concentration 1.81 microM. Incubation 1 microM their migration potential transformed morphology. RET autophosphorylation at Y1062 activation transducer activator transcription 3 by blocking Y705 phosphorylation. caused cycle arrest G0/G1 phase dephosphorylation retinoblastoma protein, but did not induce apoptosis. Western blot analysis p38, MEK/ERK, SAPK/JNK mitogen-activated protein kinase showed blocked ERK 1/2 JNK phosphorylation cytoplasm. treatment lines, combination, forskolin induced sodium (Na)/iodide (I) symporter (NIS) factors bind NIS upstream enhancer. Mechanistically, inhibition both MEK/ERK cytoplasmic individually combination an increase expression.Sunitinib appears target cytosolic suggesting these least part mechanism which inhibits causes stimulation cells.