Regulation of tumor angiogenesis by integrin-linked kinase (ILK).
We show that integrin-linked kinase (ILK) stimulates the expression of VEGF by stimulating HIF-1alpha protein expression in a PKB/Akt- and mTOR/FRAP-dependent manner. In human prostate cancer cells, knockdown of ILK expression with siRNA, or inhibition of ILK activity, results in significant inhibition of HIF-1alpha and VEGF expression. In endothelial cells, VEGF stimulates ILK activity, and inhibition of ILK expression or activity results in the inhibition of VEGF-mediated endothelial cell migration, capillary formation in vitro, and angiogenesis in vivo. Inhibition of ILK activity also inhibits prostate tumor angiogenesis and suppresses tumor growth. These data demonstrate an important and essential role of ILK in two key aspects of tumor angiogenesis: VEGF expression by tumor cells and VEGF-stimulated blood vessel formation.
Tan
Clara
C
BC Cancer Agency, The Prostate Centre at Vancouver Hospital, and Department of Biochemistry and Molecular Biology, University of British Columbia, Jack Bell Research Center, 2660 Oak Street, Vancouver, BC, V6H 3Z6 Canada.
Cruet-Hennequart
Severine
S
Troussard
Armelle
A
Fazli
Ladan
L
Costello
Penny
P
Sutton
Kym
K
Wheeler
Jeff
J
Gleave
Martin
M
Sanghera
Jasbinder
J
Dedhar
Shoukat
S
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002642:Chick Embryo; D042783:Endothelial Cells / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D029941:Fish Proteins; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D051059:PTEN Phosphohydrolase; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D000099200:Scaffold Protein ILK
D064413:3-Phosphoinositide-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D029941:Fish Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051059:PTEN Phosphohydrolase; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000099200:Scaffold Protein ILK; C497442:HIF1A protein, human; C546842:MTOR protein, human; C494918:AKT1 protein, human; C436505:Pten protein, pufferfish