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 α-
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 α-
MSH-induced apoptosis in
melanoma cells. Genetic silencing of ATG5, an autophagy regulator, by RNA interference perturbed the α-
MSH-induced apoptosis in
melanoma cells. Finally, it was delineated that α-
MSH stimulated the HIF-1α 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 α-
MSH/HIF-1α/BNIP3/BNIP3L signaling pathway.