Somatostatin inhibits tumor angiogenesis and growth via somatostatin receptor-3-mediated regulation of endothelial nitric oxide synthase and mitogen-activated protein kinase activities.
Somatostatin was reported to inhibit Kaposi's sarcoma (KS) cell (KS-Imm) xenografts through an antiangiogenic activity. Here, we show that somatostatin blocks growth of established KS-Imm tumors with the same efficacy as adriamycin, a clinically effective cytotoxic drug. Whereas KS-Imm cells do not express somatostatin receptors (SSTRs), endothelial cells express several SSTRs, in particular SSTR3. We investigated the molecular mechanisms and receptor specificity of somatostatin inhibition of angiogenesis. Somatostatin significantly inhibited angiogenesis in vivo in the matrigel sponge assay; this inhibition was mimicked by the SSTR3 agonist L-796778 and reversed by the SSTR3 antagonist BN81658, demonstrating involvement of SSTR3. In vitro experiments showed that somatostatin directly affected different endothelial cell line proliferation through a block of growth-factor-stimulated MAPK and endothelial nitric oxide (NO) synthase (eNOS) activities. BN81658 reversed somatostatin inhibition of cell proliferation, NO production, and MAPK activity, indicating that SSTR3 activation is required for the effects of somatostatin in vitro. Finally in vivo angiogenesis assays demonstrated that eNOS inhibition was a prerequisite for the antiangiogenic effects of somatostatin, because high concentrations of sodium nitroprusside, an NO donor, abolished the somatostatin effects. In conclusion, we demonstrate that somatostatin is a powerful antitumor agent in vivo that inhibits tumor angiogenesis through SSTR3-mediated inhibition of both eNOS and MAPK activities.
Florio
T
T
Farmacologia e Neuroscienze, Istituto Nazionale per la Ricerca sul Cancro, Università di Genova, 16132 Genova, Italy.
Morini
M
M
Villa
V
V
Arena
S
S
Corsaro
A
A
Thellung
S
S
Culler
M D
MD
Pfeffer
U
U
Noonan
D M
DM
Schettini
G
G
Albini
A
A
D000577:Amides / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D006728:Hormones / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009578:Nitrobenzenes / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013004:Somatostatin / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology
D000577:Amides; D006728:Hormones; C429627:L796778; D009578:Nitrobenzenes; D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3; D013004:Somatostatin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases