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First published on November 3, 2005; DOI: 10.1124/mol.105.015404

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Received for publication July 5, 2005.
Revised November 2, 2005.
Accepted for publication November 2, 2005.

Gene Transfer of Pro-opiomelanocortin Prohormone Suppressed the Growth and Metastasis of Melanoma: Involvement of {alpha}-MSH-mediated Inhibition of NF{kappa}B/COX-2 Pathway

Guei-Sheung Liu 1, Li-Fen Liu 2, Che-Jen Lin 3, Jui-Cheng Tseng 4, Ming-Ju Chuang 5, Hing-Chung Lam 5, Jenn-Kuen Lee 5, Lin-Cheng Yang 6, Julie Hwa Yu Chan 3, Shen-Long Howng 1, Ming-Hong Tai 7*

1 Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan 2 Department of Biological Science and Technology, I-Shou University, Kaohsiung, Taiwan. 3 Department of Medical Education & Research, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiw 4 Division of Allergy, Immunology, and Rheumatology, Kaohsiung Veterans General Hospital, Kaohsiung 81 5 Division of Endocrinology and Metabolism, Department of Medicine, Kaohsiung Veterans General Hospita 6 Department of Anesthesiology, E-DA Hospital, I-Shou Universit, Kaohsiung, Taiwan 7 Kaohsiung Veterans General Hospital

* Address correspondence to: E-mail: mhtai{at}isca.vghks.gov.tw

Abstract

Pro-opiomelanocortin (POMC) is a prohormone of various neuropeptides, including adrenocorticotrophic hormone (ACTH), {alpha}-melanocyte-stimulating hormone ({alpha}-MSH) and {beta}-endorphin ({beta}-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 anti-neoplastic potential of POMC gene delivery in syngenic B16-F10 melanoma model. Adenovirus-mediated POMC gene delivery in B16-F10 cells increased the release of POMC neuropeptidesin 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, prior- 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 60-70% 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 cycolooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) synthesis in melanoma cells and tumor tissues. Besides, application of NS-398, a selective COX-2 inhibitor, mimicked the anti-neoplastic functions of POMC gene transfer in melanoma. The POMC-mediated COX-2 downregulation was correlated with its inhibition of nuclear factor kappa B (NF{kappa}B) activities. Exogenous supply of {alpha}-MSH inhibited NF{kappa}B activities while application of {alpha}-MSH antagonist, GHRP-6, abolished the POMC-induced inhibition of NF{kappa}B activities and melanoma growth in mice. In summary, POMC gene delivery suppresses melanoma via {alpha}-MSH-induced inhibition of NF{kappa}B/ COX-2 pathway, thereby constituting a novel therapy for melanoma.


Key words: ACTH, Opioid, NFkappaB, Cyclooxygenases, Overexpression


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