PI3K/PTEN/AKT signaling regulates prostate tumor angiogenesis.
PI3K pathway exerts its function through its downstream molecule AKT in regulating various cell functions including cell proliferation, cell transformation, cell apoptosis, tumor growth and angiogenesis. PTEN is an inhibitor of PI3K, and its loss or mutation is common in human prostate cancer. But the direct role and mechanism of PI3K/PTEN signaling in regulating angiogenesis and tumor growth in vivo remain to be elucidated. In this study, by using chicken chorioallantoic membrane (CAM) and in nude mice models, we demonstrated that inhibition of PI3K activity by LY294002 decreased PC-3 cells-induced angiogenesis. Reconstitution of PTEN, the molecular inhibitor of PI3K in PC-3 cells inhibited angiogenesis and tumor growth. Immunohistochemical staining indicated that PTEN expression suppressed HIF-1alpha, VEGF and PCNA expression in the tumor xenographs. Similarly, expression of AKT dominant negative mutant also inhibited angiogenesis and tumor growth, and decreased the expression of HIF-1alpha and VEGF in the tumor xenographs. These results suggest that inhibition of PI3K signaling pathway by PTEN inhibits tumor angiogenesis and tumor growth. In addition, we found that AKT is the downstream target of PI3K in controlling angiogenesis and tumor growth, and PTEN could inhibit angiogenesis by regulating the expression of HIF-1 and VEGF expression through AKT activation in PC-3 cells.
Fang
Jing
J
Mary Babb Randolph Cancer Center, Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, WV 26506-9300, USA.
Ding
Min
M
Yang
Lily
L
Liu
Ling-Zhi
LZ
Jiang
Bing-Hua
BH
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D002642:Chick Embryo; D002867:Chromones / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000378:metabolism* / Q000517:prevention & control; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism