| GDC-0941 Inhibits Metastatic Characteristics of Thyroid Carcinomas by Targeting both the Phosphoinositide-3 Kinase (PI3K) and Hypoxia-Inducible Factor-1{alpha} (HIF-1{alpha}) Pathways. | |
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MedLine Citation:
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PMID: 21994956 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Context:Phosphoinositide 3-kinase (PI3K) regulates the transcription factor hypoxia-inducible factor-1 (HIF-1) in thyroid carcinoma cells. Both pathways are associated with aggressive phenotype in thyroid carcinomas.Objective:Our objective was to assess the effects of the clinical PI3K inhibitor GDC-0941 and genetic inhibition of PI3K and HIF on metastatic behavior of thyroid carcinoma cells in vitro and in vivo.Design:Vascular endothelial growth factor ELISA, HIF activity assays, proliferation studies, and scratch-wound migration and cell spreading assays were performed under various O(2) tensions [normoxia, hypoxia (1 and 0.1% O(2)), and anoxia] with or without GDC-0941 in a panel of four thyroid carcinoma cell lines (BcPAP, WRO, FTC133, and 8505c). Genetic inhibition was achieved by overexpressing phosphatase and tensin homolog (PTEN) into PTEN-null cells and by using a dominant-negative variant of HIF-1α (dnHIF). In vivo, human enhanced green fluorescence protein-expressing follicular thyroid carcinomas (FTC) were treated with GDC-0941 (orally). Spontaneous lung metastasis was confirmed by viewing enhanced green fluorescence protein-positive colonies cultured from lung tissue.Results:GDC-0941 inhibited hypoxia/anoxia-induced HIF-1α and HIF-2α expression and HIF activity in thyroid carcinoma cells. Basal (three of four cell lines) and/or hypoxia-induced (four of four) secreted vascular endothelial growth factor was inhibited by GDC-0941, whereas selective HIF targeting predominantly affected hypoxia/anoxia-mediated secretion (P < 0.05-0.0001). Antiproliferative effects of GDC-0941 were more pronounced in PTEN mutant compared with PTEN-restored cells (P < 0.05). Hypoxia increased migration in papillary cells and cell spreading/migration in FTC cells (P < 0.01). GDC-0941 reduced spreading and migration in all O(2) conditions, whereas dnHIF had an impact only on hypoxia-induced migration (P < 0.001). In vivo, GDC-0941 reduced expression of HIF-1α, phospho-AKT, GLUT-1, and lactate dehydrogenase A in FTC xenografts. DnHIF expression and GDC-0941 reduced FTC tumor growth and metastatic lung colonization (P < 0.05).Conclusions:PI3K plays a prominent role in the metastatic behavior of thyroid carcinoma cells irrespective of O(2) tension and appears upstream of HIF activation. GDC-0941 significantly inhibited the metastatic phenotype, supporting the clinical development of PI3K inhibition in thyroid carcinomas. |
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Authors:
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Natalie Burrows; Muhammad Babur; Julia Resch; Sophie Ridsdale; Melissa Mejin; Emily J Rowling; Georg Brabant; Kaye J Williams |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-10-12 |
Journal Detail:
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Title: The Journal of clinical endocrinology and metabolism Volume: - ISSN: 1945-7197 ISO Abbreviation: - Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-10-13 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0375362 Medline TA: J Clin Endocrinol Metab Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Hypoxia and Therapeutics Group (N.B., S.R., M.M., E.J.R., K.J.W.), School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PT, United Kingdom; and Department of Endocrinology (J.R., G.B.), Manchester Academic Health Science Centre, Christie Hospital, Manchester M20 4BX, United Kingdom. |
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