A molecular mimic demonstrates that phosphorylated human prolactin is a potent anti-angiogenic hormone.
S179D prolactin (PRL) is an experimentally useful mimic of naturally phosphorylated human prolactin. S179D PRL, but not unmodified PRL, was found to be anti-angiogenic in both the chorioallantoic membrane and corneal assays. Further investigation using human endothelial in vitro models showed reduced cell number, reduced tubule formation in Matrigel, and reduced migration and invasion, as a function of treatment with S179D PRL. Analysis of growth factors in human endothelial cells in response to S179D PRL showed: a decreased expression or release of endogenous PRL, heme-oxygenase-1, basic fibroblast growth factor (bFGF), angiogenin, epidermal growth factor and vascular endothelial growth factor; and an increased expression of inhibitors of matrix metalloproteases. S179D PRL also blocked signaling from bFGF in these cells. We conclude that this molecular mimic of a pituitary hormone is a potent anti-angiogenic protein, partly as a result of its ability to reduce utilization of several well-established endothelial autocrine growth loops, partly by its ability to block signaling from bFGF and partly because of its ability to decrease endothelial migration. These findings suggest that circulating levels of phosphorylated PRL may influence the progression of cancer and, furthermore, that S179D PRL may be a useful anti-angiogenic therapeutic.
Ueda
Eric
E
Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA.
Ozerdem
Ugur
U
Chen
Yen-Hao
YH
Yao
Min
M
Huang
Kuang Tzu
KT
Sun
Huiqin
H
Martins-Green
Manuela
M
Bartolini
Paolo
P
Walker
Ameae M
AM
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000378:metabolism / Q000473:pathology; D003094:Collagen; D016510:Corneal Neovascularization / Q000188:drug therapy; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007797:Laminin; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018716:Molecular Mimicry; D010766:Phosphorylation / Q000187:drug effects; D011388:Prolactin / Q000494:pharmacology*; D011509:Proteoglycans; D051381:Rats; D017207:Rats, Sprague-Dawley; D012259:Ribonuclease, Pancreatic / Q000235:genetics / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C422171:prolactin, Asp(179)-; D016222:Fibroblast Growth Factor 2; C059485:matrigel; D004815:Epidermal Growth Factor; D011388:Prolactin; D003094:Collagen; D051547:Heme Oxygenase-1; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; D020782:Matrix Metalloproteinases