Document Detail

GDC-0941 inhibits metastatic characteristics of thyroid carcinomas by targeting both the phosphoinositide-3 kinase (PI3K) and hypoxia-inducible factor-1α (HIF-1α) pathways.
MedLine Citation:
PMID:  21994956     Owner:  NLM     Status:  MEDLINE    
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.
Natalie Burrows; Muhammad Babur; Julia Resch; Sophie Ridsdale; Melissa Mejin; Emily J Rowling; Georg Brabant; Kaye J Williams
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2011-10-12
Journal Detail:
Title:  The Journal of clinical endocrinology and metabolism     Volume:  96     ISSN:  1945-7197     ISO Abbreviation:  J. Clin. Endocrinol. Metab.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-06     Completed Date:  2012-02-09     Revised Date:  2014-03-14    
Medline Journal Info:
Nlm Unique ID:  0375362     Medline TA:  J Clin Endocrinol Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  E1934-43     Citation Subset:  AIM; IM    
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MeSH Terms
Antineoplastic Agents / pharmacology*
Carcinoma / enzymology,  pathology,  secondary*
Cell Hypoxia
Cell Movement / drug effects
Cell Proliferation / drug effects
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Indazoles / pharmacology*
PTEN Phosphohydrolase / metabolism
Phosphatidylinositol 3-Kinases / metabolism*
Signal Transduction / drug effects*
Sulfonamides / pharmacology*
Thyroid Neoplasms / enzymology,  metabolism,  pathology*
Tumor Cells, Cultured
Vascular Endothelial Growth Factor A / metabolism
Grant Support
082794//Wellcome Trust; 100140//Wellcome Trust; C7820/A8696//Cancer Research UK
Reg. No./Substance:
0/2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; 0/Antineoplastic Agents; 0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Indazoles; 0/Sulfonamides; 0/Vascular Endothelial Growth Factor A; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC Phosphohydrolase

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