17alpha-estradiol-induced VEGF-A expression in rat pituitary tumor cells is mediated through ER independent but PI3K-Akt dependent signaling pathway.
17alpha-E(2), a weak estrogen exhibited both agonistic and antagonistic effects, and caused a time- and dose-dependent induction of VEGF-A mRNA expression in GH3 rat pituitary tumor cells. This effect was unaffected by the presence of the pure estrogen receptor antagonist ICI 182,780 but was specifically blocked by a protein synthesis inhibitor puromycin. Inhibition of phosphatidylinositol-3 kinase (PI3K) activity by wortmannin decreased the effect of 17alpha-E(2) on VEGF-A mRNA expression. This inhibitor also blocked the increase in phosphorylation of Akt induced by exposure to 17alpha-E(2). In contrast, exposure to the MAP kinase inhibitor, U0126, had no impact on 17alpha-E(2)-induced VEGF-A mRNA expression. Taken together, these studies indicate that like potent estrogens 17alpha-E(2) up-regulates VEGF-A mRNA expression in estrogen responsive GH3 rat pituitary tumor cells, but this induction is not mediated through a classical estrogen receptor pathway. PI3K-Akt signaling pathway is required for the induction of VEGF-A mRNA in GH3 cells by 17alpha-E(2).
Banerjee
Snigdha
S
Cancer Research Unit, Research Division 151, V.A. Medical Center, Kansas City, MO 64128, USA.
Saxena
Neela
N
Sengupta
Krishanu
K
Banerjee
Sushanta K
SK
D000730:Androstadienes / Q000494:pharmacology; D043925:Angiogenesis Inducing Agents / Q000235:genetics*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D000077267:Fulvestrant; D015870:Gene Expression / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011691:Puromycin / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D000077191:Wortmannin
D000730:Androstadienes; D043925:Angiogenesis Inducing Agents; D004791:Enzyme Inhibitors; D004958:Estradiol; D020847:Estrogen Receptor Modulators; D000077267:Fulvestrant; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011691:Puromycin; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D042461:Vascular Endothelial Growth Factor A; D000077191:Wortmannin; C467498:vascular endothelial growth factor A, rat; C494920:Akt1 protein, rat