PMID- 21994956
OWN - NLM
STAT- MEDLINE
DCOM- 20120209
LR  - 20211020
IS  - 1945-7197 (Electronic)
IS  - 0021-972X (Linking)
VI  - 96
IP  - 12
DP  - 2011 Dec
TI  - GDC-0941 inhibits metastatic characteristics of thyroid carcinomas by targeting 
      both the phosphoinositide-3 kinase (PI3K) and hypoxia-inducible factor-1alpha 
      (HIF-1alpha) pathways.
PG  - E1934-43
LID - 10.1210/jc.2011-1426 [doi]
AB  - 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-1alpha (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-1alpha and HIF-2alpha 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-1alpha, 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.
FAU - Burrows, Natalie
AU  - Burrows N
AD  - Hypoxia and Therapeutics Group, School of Pharmacy and Pharmaceutical Sciences, 
      University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
FAU - Babur, Muhammad
AU  - Babur M
FAU - Resch, Julia
AU  - Resch J
FAU - Ridsdale, Sophie
AU  - Ridsdale S
FAU - Mejin, Melissa
AU  - Mejin M
FAU - Rowling, Emily J
AU  - Rowling EJ
FAU - Brabant, Georg
AU  - Brabant G
FAU - Williams, Kaye J
AU  - Williams KJ
LA  - eng
GR  - 100140/Wellcome Trust/United Kingdom
GR  - C7820/A8696/CRUK_/Cancer Research UK/United Kingdom
GR  - 082794/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20111012
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 
      (2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Indazoles)
RN  - 0 (Sulfonamides)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Carcinoma/enzymology/pathology/*secondary
MH  - Cell Hypoxia
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Female
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Indazoles/*pharmacology
MH  - Mice
MH  - PTEN Phosphohydrolase/metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Signal Transduction/*drug effects
MH  - Sulfonamides/*pharmacology
MH  - Thyroid Neoplasms/enzymology/metabolism/*pathology
MH  - Tumor Cells, Cultured
MH  - Vascular Endothelial Growth Factor A/metabolism
EDAT- 2011/10/14 06:00
MHDA- 2012/02/10 06:00
CRDT- 2011/10/14 06:00
PHST- 2011/10/14 06:00 [entrez]
PHST- 2011/10/14 06:00 [pubmed]
PHST- 2012/02/10 06:00 [medline]
AID - jc.2011-1426 [pii]
AID - 10.1210/jc.2011-1426 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2011 Dec;96(12):E1934-43. doi: 10.1210/jc.2011-1426. 
      Epub 2011 Oct 12.