ectin-3 Promotes Chronic Activation of K-Ras and Ther erentiation Block in Malignant Thyroid Carcinomas

nloaded plastic thyroid carcinomas are deadly tumors that are highly invasive, particularly into the bones. gh oncogenic Ras can transform thyroid cells into a severely malignant phenotype, thyroid carcinoo not usually harbor ras gene mutations. Therefore, it is not known whether chronically active Ras butes to thyroid carcinoma cell proliferation, although galectin-3 (Gal-3), which is strongly expressed roid carcinomas but not in benign tumors or normal glands, is known to act as a K-Ras chaperone that zes and drives K-Ras.GTP nanoclustering and signal robustness. Here, we examined the possibility yroid carcinomas expressing high levels of Gal-3 exhibit chronically active K-Ras. Using cell lines reting three types of malignant thyroid tumors—papillary, follicular, and anaplastic—we investigated the le correlation between Gal-3 expression and active Ras content, and then examined the therapeutic ial of the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS; Salirasib) for thyroid carcinoma. id carcinoma cells strongly expressing Gal-3 showed high levels of K-Ras.GTP expression, and .GTP transmitted strong signals to extracellular signal-regulated kinase. FTS disrupted interactions en Gal-3 and K.Ras, strongly reduced K-Ras.GTP and phospho-extracellular signal-regulated kinase sion, and enhanced the expression of the cell cycle inhibitor p21 as well as of the thyroid transcription 1, which is involved in thyroid cell differentiation. FTS also inhibited anaplastic thyroid carcinoma cell ration in vitro and tumor growth in nude mice. We conclude that wild-type K-Ras.GTP in association prolife with Gal-3 contributes to thyroid carcinoma malignancy and that Ras inhibition might be a useful treatment strategy against these deadly tumors. Mol Cancer Ther; 9(8); 2208–19. ©2010 AACR.