Pro-opiomelanocortin (POMC) is a prohormone of various neuropeptides, including corticotropin, ␣-melanocyte-stimulating hormone (␣-MSH), and ␤-endorphin (␤-EP). POMC neuropeptides are potent inflammation inhibitors and immunosuppressants and may exert opposite influences during tumorigenesis. However, the role of POMC expression in carcinogenesis remains elusive. We evaluated the antineoplastic potential of POMC gene delivery in a syngenic B16-F10 melanoma model. Adenovirus-mediated POMC gene delivery in B16-F10 cells increased the release of POMC neuropeptides in cultured media, which differentially regulated the secretion of pro-and anti-inflammatory cytokines in lymphocytes. POMC gene transfer significantly reduced the anchorage-independent growth of melanoma cells. Moreover, pre-or post-treatment with POMC gene delivery effectively retarded the melanoma growth in mice. Intravenous injection of POMC-transduced B16-F10 cells resulted in reduced foci formation in lung by 60 to 70% of control. The reduced metastasis of POMC-transduced B16-F10 cells could be attributed to their attenuated migratory and adhesive capabilities. POMC gene delivery reduced the cyclooxygenase-2 (COX-2) expression and prostaglandin (PG) E 2 synthesis in melanoma cells and tumor tissues. In addition, application of NS-398, a selective COX-2 inhibitor, mimicked the antineoplastic functions of POMC gene transfer in melanoma. The POMC-mediated COX-2 down-regulation was correlated with its inhibition of nuclear factor B (NFB) activities. Exogenous supply of ␣-MSH inhibited NFB activities, whereas application of the ␣-MSH antagonist growth hormone-releasing peptide-6 (GHRP-6) abolished the POMC-induced inhibition of NFB activities and melanoma growth in mice. In summary, POMC gene delivery suppresses melanoma via ␣-MSH-induced inhibition of NFB/COX-2 pathway, thereby constituting a novel therapy for melanoma.POMC is a multifunctional polycistronic gene located on human chromosome 2p23.3. POMC is a 31 kDa prohormone that is processed into various neuropeptides, including corticotropin, melanotropins (␣-, ␤-, and ␥-MSH), lipotropins, and ␤-endorphin (␤-EP) (Solomon, 1999;Catania et al., 2004b). POMC peptides possess pleiotropic functions including pigmentation, adrenocortical function, regulation of energy stores, the immune system, and the central and peripheral

Pro-opiomelanocortin (POMC) is expressed in the nucleus tractus solitarii (NTS) of the brainstem, where nitric oxide (NO) plays an important role in cardiovascular regulation. The POMCderived neuropeptides and their receptors are important regulators of energy homeostasis and cardiovascular functions in the central nervous system. In this study, we investigated the cardiovascular effect of ␣-melanocyte-stimulating hormone (␣-MSH), a POMC-derived neuropeptide, and its relationship with NO pathway in the NTS of spontaneously hypertensive rats (SHR). Unilateral microinjection of ␣-MSH (0.3-300 pmol) into the NTS resulted in a dose-dependent hypotension and bradycardia in urethane-anesthetized SHR. The ␣-MSH-induced hy The pro-opiomelanocortin (POMC) system and its derived melanocortins are recognized as important regulators in many physiological processes, including of pigmentation, inflammation, energy homeostasis, immunomodulation, memory, and sexual function (Gantz and Fong, 2003;Luger et al., 2003;Matsumura et al., 2003;Raffin-Sanson et al., 2003;Voisey et al., 2003;Catania et al., 2004;Ellacott and Cone, 2004;Cone, 2005). POMC is expressed at two locations in the brain: the arcuate nucleus of the hypothalamus and the nucleus tractus solitarii (NTS) of the brainstem (Ellacott and Cone, 2004;Cone, 2005). The NTS is a central site where various stimuli of baroreceptor reflexes and satiety integrate, thereby facilitating the cross-talk between cardiovascular regulation and energy homeostasis (Gordon, 1990;Appleyard et al., 2005;Cone, 2005). The POMC-derived neuropeptides in the NTS have been proposed to regulate the sympathetic activity and blood pressure (BP) (Li et al