The 16K fragment of prolactin specifically inhibits basal or fibroblast growth factor stimulated growth of capillary endothelial cells.
Intact 23 kilodalton (kDa), rat PRL is enzymatically cleaved in many target tissues to a 16 kDa (16K PRL) and an 8 kDa fragment. After reduction of an internal disulfide bond the fragments are released. 16K PRL was shown to be a potent mitogen on mammary epithelial cells via PRL receptors. Since estradiol-induced prolactinomas develop a new blood supply we tested the action of intact PRL and 16K PRL on growth of new vessels (angiogenesis). The angiogenic action of intact PRL and 16K PRL was tested in cultured bovine brain and adrenal cortex endothelial cells. Basal (b) or b-fibroblast growth factor (FGF) stimulated growth was estimated by counting cells or measuring the level of incorporation of 3H-thymidine into DNA. Paradoxically, 16K PRL inhibited the basal and FGF-stimulated growth of cultured endothelial cells in a dose-dependent fashion. Intact PRL or the cleaved but not reduced PRL were inactive even at a 100-fold higher concentration. When reformation of disulfide bonds was inhibited by carbamidomethylation of 16K PRL the preparations were more potent. 16K PRL had no effect on the mitogenic action of bFGF on baby hamster kidney cells which are known to have FGF receptors. These data demonstrate that in vitro 16K PRL is a potent and specific angiolytic factor, i.e. it inhibits angiogenesis. Furthermore, the action of 16K PRL does not appear to be via the known PRL or FGF receptors. Since angiogenesis is an essential component of tumor growth 16K PRL has potential as a therapeutic agent for the treatment of cancer.
Ferrara
N
N
Reproductive Endocrinology Center, University of California, San Francisco 94143.
Clapp
C
C
Weiner
R
R
D000302:Adrenal Cortex / Q000098:blood supply; D000818:Animals; D001639:Bicarbonates; D002196:Capillaries; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply; D004220:Disulfides / Q000378:metabolism; D004229:Dithiothreitol; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D005260:Female; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D019791:Guanidine; D006146:Guanidines; D008970:Molecular Weight; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011388:Prolactin / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
D001639:Bicarbonates; D004220:Disulfides; D006146:Guanidines; D010446:Peptide Fragments; C027043:ammonium bicarbonate; D005346:Fibroblast Growth Factors; D011388:Prolactin; D019791:Guanidine; D004229:Dithiothreitol