RT Journal Article
SR Electronic
T1 Gene Transfer of Pro-opiomelanocortin Prohormone Suppressed the Growth and Metastasis of Melanoma: Involvement of α-Melanocyte-Stimulating Hormone-Mediated Inhibition of the Nuclear Factor κB/Cyclooxygenase-2 Pathway
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 440
OP 451
DO 10.1124/mol.105.015404
VO 69
IS 2
A1 Guei-Sheung Liu
A1 Li-Fen Liu
A1 Che-Jen Lin
A1 Jui-Cheng Tseng
A1 Ming-Ju Chuang
A1 Hing-Chung Lam
A1 Jenn-Kuen Lee
A1 Lin-Cheng Yang
A1 Julie Hwa Yu Chan
A1 Shen-Long Howng
A1 Ming-Hong Tai
YR 2006
UL http://molpharm.aspetjournals.org/content/69/2/440.abstract
AB Pro-opiomelanocortin (POMC) is a prohormone of various neuropeptides, including corticotropin, α-melanocyte-stimulating hormone (α-MSH), and β-endorphin (β-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) E2 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 κB (NFκB) activities. Exogenous supply of α-MSH inhibited NFκB activities, whereas application of the α-MSH antagonist growth hormone-releasing peptide-6 (GHRP-6) abolished the POMC-induced inhibition of NFκB activities and melanoma growth in mice. In summary, POMC gene delivery suppresses melanoma via α-MSH-induced inhibition of NFκB/COX-2 pathway, thereby constituting a novel therapy for melanoma.