Abstract
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.
Highlights
Hypoxia is a common characteristic of pathological features presenting in solid tumors and is associated with a poor outcome
POMC gene therapy elicits autophagy in melanoma in vivo Because it is known that POMC gene therapy induces apoptosis in melanoma via α-MSH during hypoxic challenge[29], we would like to elucidate whether autophagy occurred and participated in POMC-induced melanoma suppression
It was revealed that a strong LC3 staining was observed in adenovirus (Ad)-POMC-infected tumors compared with Ad-green fluorescent protein (GFP)-infected tumors, and it was correlated with low density of CD31-positive microvessels, implying that POMC-induced autophagy might occur under hypoxic stress (Fig. 1b)
Summary
Hypoxia is a common characteristic of pathological features presenting in solid tumors and is associated with a poor outcome. Tumor cells are well adapted to moderate hypoxia by inducing several genes involved in angiogenesis, glycolysis, glucose uptake and metastasis[1]. In complex conditions such as glucose deprivation or acidosis, hypoxia is capable of inducing apoptosis and autophagic cell death through a hypoxiainducible factor-1 (HIF-1)-independent manner or reactive oxygen species (ROS) stimuli[2,3,4,5]. Autophagy is a self-degradative process for the cellular stress adaptation response that maintains cell homeostasis and protection[8]. The autophagic process initially requires the dissociated Beclin-1 from Bcl-2 or Bcl-XL binds to class ΙΙΙ phosphatidylinositol 3-kinase (PIK3C3 or Vps34) that forms an initiation complex and recruits autophagy-related protein 7 (ATG7) to the developing phagopore. Autophagosomal elongation recruits two ubiquitin-like conjugation systems, ATG12ATG5 and subsequent phosphatidylethanolamine conjugated form of the microtubule-associated protein light
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