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SU5416 inhibited VEGF and HIF-1alpha expression through the PI3K/AKT/p70S6K1 signaling pathway.

Abstract
Ovarian cancer has the highest mortality rate of any gynecological disease affecting women in Western countries. VEGF is a crucial inducer of angiogenesis both in vivo and in vitro. VEGF is commonly upregulated in ovarian cancer and is regulated by HIF-1. SU5416 is known to inhibit various stages of tumor growth. In this study, we show that SU5416 inhibited VEGF mRNA expression in ovarian cancer cells in a dose-dependent manner. SU5416 inhibited VEGF expression at the transcriptional level through the HIF-1 DNA binding site. HIF-1 is composed of HIF-1alpha and HIF-1beta subunits. SU5416 specifically decreased HIF-1alpha, but not HIF-1beta protein levels. To understand the signaling pathways regulating SU5416-inhibited VEGF and HIF-1alpha expression, we found that SU5416 inhibited PI3K activity. AKT is a downstream target of PI3K. We found that SU5416 also inhibited AKT and p70S6K1 activation and activity in a dose-dependent manner. These results demonstrate that SU5416 inhibited VEGF and HIF-1alpha expression through the inhibition of PI3K/AKT/p70S6K1 pathway in ovarian cancer cells. These results indicate that SU5416 may be an effective agent for ovarian cancer treatment through the inhibition of VEGF and HIF-1 expression, and the activation of PI3K/AKT/p70S6K1 signaling pathway.
AuthorsXiao-Song Zhong, Jenny Z Zheng, Eddie Reed, Bing-Hua Jiang
JournalBiochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 324 Issue 2 Pg. 471-80 (Nov 12 2004) ISSN: 0006-291X [Print] United States
PMID15474452 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Enzyme Inhibitors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indoles
  • Proto-Oncogene Proteins
  • Pyrroles
  • RNA, Messenger
  • Tetrazolium Salts
  • Thiazoles
  • Transcription Factors
  • Vascular Endothelial Growth Factor A
  • RNA
  • Semaxinib
  • Luciferases
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • thiazolyl blue
Topics
  • Binding Sites
  • Blotting, Northern
  • Cell Line, Tumor
  • Cell Proliferation
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors (pharmacology)
  • Female
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Immunoblotting
  • Indoles (pharmacology)
  • Luciferases (metabolism)
  • Neovascularization, Pathologic
  • Ovarian Neoplasms (drug therapy, enzymology, metabolism)
  • Phosphatidylinositol 3-Kinases (metabolism)
  • Phosphorylation
  • Plasmids (metabolism)
  • Protein Binding
  • Protein Serine-Threonine Kinases (metabolism)
  • Proto-Oncogene Proteins (metabolism)
  • Proto-Oncogene Proteins c-akt
  • Pyrroles (pharmacology)
  • RNA (metabolism)
  • RNA, Messenger (metabolism)
  • Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
  • Signal Transduction
  • Tetrazolium Salts (pharmacology)
  • Thiazoles (pharmacology)
  • Time Factors
  • Transcription Factors (antagonists & inhibitors)
  • Transcriptional Activation
  • Transfection
  • Up-Regulation
  • Vascular Endothelial Growth Factor A (antagonists & inhibitors, metabolism)

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