Inhibition of Tie-2 signaling induces endothelial cell apoptosis, decreases Akt signaling, and induces endothelial cell expression of the endogenous anti-angiogenic molecule, thrombospondin-1.
Small molecule inhibitors of endothelial cell specific tyrosine kinases are currently under investigation as potential means to block tumor angiogenesis. We have investigated the utility of blocking Tie-2 signaling in endothelial cells as a potential anti-angiogenic strategy. We have found that interruption of Tie-2 signaling either via RNAi or overexpression of a kinase-dead Tie-2 led to loss of endothelial cell viability, even in the presence of serum. Mechanistically, this is linked to a block in Akt signaling and increased thrombospondin expression. Thrombospondins are endogenous anti-angiogenic matricellular proteins known to regulate tumor growth and angiogenesis. We observed that both Tie-2 and subsequent PI3Kinase signaling regulates thrombospondin-1 expression. These data have lead to the model that Angiopoietin signaling through Tie-2 activates PI3Kinase/Akt, which represses thrombospondin expression. Thus, targeting Tie-2 with small molecules maybe efficacious as an anti-angiogenic therapy.
Niu
Qi
Q
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Perruzzi
Carole
C
Voskas
Daniel
D
Lawler
Jack
J
Dumont
Daniel J
DJ
Benjamin
Laura E
LE
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics*; D018929:Cell Culture Techniques; D002470:Cell Survival; D017931:DNA Primers; D042783:Endothelial Cells / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000503:physiopathology; D009389:Neovascularization, Pathologic; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt; D042787:Receptor, TIE-2 / Q000502:physiology*; D015398:Signal Transduction; D019700:Thrombospondin 1 / Q000096:biosynthesis* / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D019700:Thrombospondin 1; D011505:Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt