title: Galectin-3 promotes chronic activation of K-Ras and differentiation block in malignant thyroid carcinomas.
abstract: Anaplastic thyroid carcinomas are deadly tumors that are highly invasive, particularly into the bones. Although oncogenic Ras can transform thyroid cells into a severely malignant phenotype, thyroid carcinomas do not usually harbor ras gene mutations. Therefore, it is not known whether chronically active Ras contributes to thyroid carcinoma cell proliferation, although galectin-3 (Gal-3), which is strongly expressed in thyroid carcinomas but not in benign tumors or normal glands, is known to act as a K-Ras chaperone that stabilizes and drives K-Ras.GTP nanoclustering and signal robustness. Here, we examined the possibility that thyroid carcinomas expressing high levels of Gal-3 exhibit chronically active K-Ras. Using cell lines representing three types of malignant thyroid tumors--papillary, follicular, and anaplastic--we investigated the possible correlation between Gal-3 expression and active Ras content, and then examined the therapeutic potential of the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS; Salirasib) for thyroid carcinoma. Thyroid carcinoma cells strongly expressing Gal-3 showed high levels of K-Ras.GTP expression, and K-Ras.GTP transmitted strong signals to extracellular signal-regulated kinase. FTS disrupted interactions between Gal-3 and K.Ras, strongly reduced K-Ras.GTP and phospho-extracellular signal-regulated kinase expression, and enhanced the expression of the cell cycle inhibitor p21 as well as of the thyroid transcription factor 1, which is involved in thyroid cell differentiation. FTS also inhibited anaplastic thyroid carcinoma cell proliferation in vitro and tumor growth in nude mice. We conclude that wild-type K-Ras.GTP in association with Gal-3 contributes to thyroid carcinoma malignancy and that Ras inhibition might be a useful treatment strategy against these deadly tumors.
authors.affiliation: Department of Neurobiology, Tel Aviv University, 69978 Tel-Aviv, Israel.
authors.forename: Ran
authors.initials: R
authors.lastname: Levy
authors.forename: Meital
authors.initials: M
authors.lastname: Grafi-Cohen
authors.forename: Zaki
authors.initials: Z
authors.lastname: Kraiem
authors.forename: Yoel
authors.initials: Y
authors.lastname: Kloog
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005204:Farnesol / Q000031:analogs & derivatives / Q000494:pharmacology; D037502:Galectin 3 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D012459:Salicylates / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D037502:Galectin 3; C117307:KRAS protein, human; C000614412:NKX2-1 protein, human; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012459:Salicylates; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D006160:Guanosine Triphosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins