Document Detail


Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics.
MedLine Citation:
PMID:  10749120     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Dysregulated signal transduction from receptor tyrosine kinases to phosphatidylinositol 3-kinase (PI3K), AKT (protein kinase B), and its effector FKBP-rapamycin-associated protein (FRAP) occurs via autocrine stimulation or inactivation of the tumor suppressor PTEN in many cancers. Here we demonstrate that in human prostate cancer cells, basal-, growth factor-, and mitogen-induced expression of hypoxia-inducible factor 1 (HIF-1) alpha, the regulated subunit of the transcription factor HIF-1, is blocked by LY294002 and rapamycin, inhibitors of PI3K and FRAP, respectively. HIF-1-dependent gene transcription is blocked by dominant-negative AKT or PI3K and by wild-type PTEN, whereas transcription is stimulated by constitutively active AKT or dominant-negative PTEN. LY294002 and rapamycin also inhibit growth factor- and mitogen-induced secretion of vascular endothelial growth factor, the product of a known HIF-1 target gene, thus linking the PI3K/PTEN/AKT/FRAP pathway, HIF-1, and tumor angiogenesis. These data indicate that pharmacological agents that target PI3K, AKT, or FRAP in tumor cells inhibit HIF-1alpha expression and that such inhibition may contribute to therapeutic efficacy.
Authors:
H Zhong; K Chiles; D Feldser; E Laughner; C Hanrahan; M M Georgescu; J W Simons; G L Semenza
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  60     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2000 Mar 
Date Detail:
Created Date:  2000-05-04     Completed Date:  2000-05-04     Revised Date:  2012-06-22    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1541-5     Citation Subset:  IM    
Affiliation:
The Johns Hopkins Oncology Center, Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
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MeSH Terms
Descriptor/Qualifier:
Anoxia / physiopathology
Carrier Proteins*
Chromones / pharmacology
Culture Media, Serum-Free / pharmacology
DNA-Binding Proteins / biosynthesis*,  drug effects
Endothelial Growth Factors / biosynthesis,  pharmacology
Enzyme Inhibitors / pharmacology
Enzyme-Linked Immunosorbent Assay
Epidermal Growth Factor / genetics,  pharmacology,  physiology
Humans
Hypoxia-Inducible Factor 1
Hypoxia-Inducible Factor 1, alpha Subunit
Immunophilins / genetics,  physiology
Lymphokines / biosynthesis,  pharmacology
Male
Morpholines / pharmacology
Neovascularization, Pathologic / metabolism
Nuclear Proteins / biosynthesis*,  drug effects
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinases / antagonists & inhibitors,  genetics,  physiology
Phosphoric Monoester Hydrolases / genetics,  physiology
Phosphotransferases (Alcohol Group Acceptor)*
Prostatic Neoplasms / drug therapy,  metabolism*,  pathology
Protein-Serine-Threonine Kinases*
Proto-Oncogene Proteins / genetics,  physiology
Proto-Oncogene Proteins c-akt
Signal Transduction / drug effects,  genetics,  physiology*
TOR Serine-Threonine Kinases
Tetradecanoylphorbol Acetate / pharmacology
Transcription Factors*
Tumor Cells, Cultured / drug effects,  metabolism
Tumor Suppressor Proteins*
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
Grant Support
ID/Acronym/Agency:
CA-58236/CA/NCI NIH HHS; R01-HL55338/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Carrier Proteins; 0/Chromones; 0/Culture Media, Serum-Free; 0/DNA-Binding Proteins; 0/Endothelial Growth Factors; 0/Enzyme Inhibitors; 0/HIF1A protein, human; 0/Hypoxia-Inducible Factor 1; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Lymphokines; 0/Morpholines; 0/Nuclear Proteins; 0/Proto-Oncogene Proteins; 0/Transcription Factors; 0/Tumor Suppressor Proteins; 0/Vascular Endothelial Growth Factor A; 0/Vascular Endothelial Growth Factors; 154447-36-6/2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; 16561-29-8/Tetradecanoylphorbol Acetate; 62229-50-9/Epidermal Growth Factor; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.1/MTOR protein, human; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.11.1/AKT1 protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.1.3.-/Phosphoric Monoester Hydrolases; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase; EC 5.2.1.8/Immunophilins

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