title: Functional involvement of β3-adrenergic receptors in melanoma growth and vascularization.
abstract: β-adrenergic signaling is thought to facilitate cancer progression and blockade of β-adrenergic receptors (β-ARs) may slow down tumor growth. A possible role of β3-ARs in tumor growth has not been investigated so far and the lack of highly specific antagonists makes difficult the evaluation of this role. In the present study, β3-AR expression in mouse B16F10 melanoma cells was demonstrated and the effects of two widely used β3-AR blockers, SR59230A and L-748,337, were evaluated in comparison with propranolol, a β1-/β2-AR blocker with poor affinity for β3-ARs, and with siRNAs targeting specific β-ARs. Both SR59230A and L-748,337 reduced cell proliferation and induced apoptosis, likely through the involvement of the inducible isoform of nitric oxide synthase. In addition, hypoxia upregulated β3-ARs and vascular endothelial growth factor (VEGF) in B16F10 cells, whereas SR59230A or L-748,337 prevented the hypoxia-induced VEGF upregulation. Melanoma was induced in mice by inoculation of B16F10 cells. Intra-tumor injections of SR59230A or L-748,337 significantly reduced melanoma growth by reducing cell proliferation and stimulating apoptosis. SR59230A or L-748,337 treatment also resulted in significant decrease of the tumor vasculature. The decrease in tumor vasculature was due to apoptosis of endothelial cells and not to downregulation of angiogenic factors. These results demonstrate that SR59230A and L-748,337 significantly inhibit melanoma growth by reducing tumor cell proliferation and activating tumor cell death. In addition, both drugs reduce tumor vascularization by inducing apoptosis of endothelial cells. Together, these findings indicate β3-ARs as promising, novel targets for anti-cancer therapy.
  
  
  CONCLUSIONS
  β3-ARs are expressed in B16F10 melanoma cells β3-ARs are involved in B16F10 cell proliferation and apoptosis Reduced β3-AR function decreases the growth of melanoma induced by B16F10 cell inoculation Drugs targeting β3-ARs reduce tumor vasculature β3-ARs can be regarded as promising, novel targets for anti-cancer therapy.
authors.affiliation: Department of Biology, University of Pisa, via San Zeno, 31, 56127, Pisa, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Dal Monte
authors.forename: Giovanni
authors.initials: G
authors.lastname: Casini
authors.forename: Luca
authors.initials: L
authors.lastname: Filippi
authors.forename: Grazia Paola
authors.initials: GP
authors.lastname: Nicchia
authors.forename: Maria
authors.initials: M
authors.lastname: Svelto
authors.forename: Paola
authors.initials: P
authors.lastname: Bagnoli
mesh_terms: D058673:Adrenergic beta-3 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015687:Cell Hypoxia; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008546:Melanoma, Experimental; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011412:Propanolamines / Q000008:administration & dosage / Q000494:pharmacology; D034622:RNA Interference; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C097869:3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate; D058673:Adrenergic beta-3 Receptor Antagonists; D011412:Propanolamines; D022702:Receptors, Adrenergic, beta-3; D042461:Vascular Endothelial Growth Factor A
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