Journal
CELL DEATH DISCOVERY
Volume 4, Issue -, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41420-018-0070-5
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Funding
- National Research Program for Biopharmaceuticals [MOST-105-2314-B-075B-002, MOST-105-2325-B110-002]
- Kaohsiung Veterans General Hospital, Taiwan [VGHNSU104-003, VGHNSU105-001, VGHNSU106-004]
- National Sun Yat Sen University-Kaohsiung Medical University [105P-023]
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Hypoxia in tumors is known to trigger the pro-survival pathways such as autophagy. Systemic proopiomelanocortin (POMC) gene therapy suppresses melanoma through apoptosis induction and neovascularization blockage. In this study, we investigated the crosstalk between autophagic and apoptotic signaling in POMC-mediated melanoma suppression. By histological and immunoblot analysis, it was shown that POMC-treated melanoma tissues exhibited the prominent LC3 immunostaining, which was correlated with reduced CD31-positive tumor vascularization. Such autophagy induction could be recapitulated in melanoma cells receiving POMC gene delivery and hypoxia-mimicking agent cobalt chloride (CoCl2). We then utilized the POMC-derived peptide alpha-MSH with CoCl2 to elicit the autophagy as well as apoptosis in cultured melanoma cells. To delineate the role of autophagy during cell death, application of autophagy-inducer rapamycin enhanced, whereas autophagy inhibitor 3-MA attenuated, the alpha-MSH-induced apoptosis in melanoma cells. Genetic silencing of ATG5, an autophagy regulator, by RNA interference perturbed the alpha-MSH-induced apoptosis in melanoma cells. Finally, it was delineated that alpha-MSH stimulated the HIF-1 alpha signaling as well as the expression of BNIP3/BNIP3L, thereby promoting the autophagy and apoptosis in melanoma cells. Therefore, the present study unveiled a unique function of autophagy in promoting cell death during POMC-mediated melanoma suppression via alpha-MSH/HIF-1 alpha/BNIP3/BNIP3L signaling pathway.
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