Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells.
Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that has been shown to act as an endothelial cell mitogen as well as a vascular permeability factor. Several recent reports have also implicated VEGF as a major survival factor for endothelial cells during angiogenesis and vasculogenesis along with other growth factors such as bFGF and angiopoietin-1. VEGF has been shown to mediate this additional function, at least in part through the induction of bcl-2 and the activation of the PI3 kinase-Akt/PKB signaling pathway. We report here that VEGF can also mediate the induction/upregulation of members of a newly discovered family of antiapoptotic proteins, namely the Inhibitors of Apoptosis (IAP), in vascular endothelial cells. We show that VEGF(165) leads to the induction of XIAP (2.9-fold) and survivin (19.1-fold) protein in human umbilical vein endothelial cells (HUVECs). In contrast, bFGF had little effect on XIAP expression, but produced approximately a 10-fold induction on survivin. VEGF-dependent upregulation of survivin could be prevented by cell cycle arrest in the G1 and S phases. These findings implicate that the survival and mitotic functions of VEGF in an angiogenic context may be more intrinsically related than previously anticipated. Moreover, they also raise the possibility of therapeutically targeting XIAP or survivin in antiangiogenic therapy as a means of suppressing tumor growth, in addition to directly targeting tumor cells which express these survival proteins.
Tran
J
J
Division of Cancer Biology Research, Sunnybrook and Women's College Health Sciences Centre, S-218 Research Building, 2075 Bayview Avenue, Toronto, Ontario, M4N 3M5, Canada.
Rak
J
J
Sheehan
C
C
Saibil
S D
SD
LaCasse
E
E
Korneluk
R G
RG
Kerbel
R S
RS
D017209:Apoptosis; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008222:Lymphokines / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D014176:Protein Biosynthesis; D011506:Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor; D000077022:Survivin; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051636:X-Linked Inhibitor of Apoptosis Protein
C107489:BIRC5 protein, human; D016228:Endothelial Growth Factors; D051034:Inhibitor of Apoptosis Proteins; D008222:Lymphokines; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D017978:Receptors, Growth Factor; D000077022:Survivin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor