Functional involvement of β3-adrenergic receptors in melanoma growth and vascularization

beta-adrenergic signaling is thought to facilitate cancer progression and blockade of beta-adrenergic receptors (beta-ARs) may slow down tumor growth. A possible role of beta 3-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, beta 3-AR expression in mouse B16F10 melanoma cells was demonstrated and the effects of two widely used beta 3-AR blockers, SR59230A and L-748,337, were evaluated in comparison with propranolol, a beta 1-/beta 2-AR blocker with poor affinity for beta 3-ARs, and with siRNAs targeting specific beta-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 beta 3-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 beta 3-ARs as promising, novel targets for anti-cancer therapy. Key message beta 3-ARs are expressed in B16F10 melanoma cells beta 3-ARs are involved in B16F10 cell proliferation and apoptosis Reduced beta 3-AR function decreases the growth of melanoma induced by B16F10 cell inoculation Drugs targeting beta 3-ARs reduce tumor vasculature beta 3-ARs can be regarded as promising, novel targets for anti-cancer therapy.