AMPK promotes survival of c-Myc-positive melanoma cells by suppressing oxidative stress.
Although c-Myc is essential for melanocyte development, its role in cutaneous melanoma, the most aggressive skin cancer, is only partly understood. Here we used the NrasINK4a-/- mouse melanoma model to show that c-Myc is essential for tumor initiation, maintenance, and metastasis. c-Myc-expressing melanoma cells were preferentially found at metastatic sites, correlated with increased tumor aggressiveness and high tumor initiation potential. Abrogation of c-Myc caused apoptosis in primary murine and human melanoma cells. Mechanistically, c-Myc-positive melanoma cells activated and became dependent on the metabolic energy sensor AMP-activated protein kinase (AMPK), a metabolic checkpoint kinase that plays an important role in energy and redox homeostasis under stress conditions. AMPK pathway inhibition caused apoptosis of c-Myc-expressing melanoma cells, while AMPK activation protected against cell death of c-Myc-depleted melanoma cells through suppression of oxidative stress. Furthermore, TCGA database analysis of early-stage human melanoma samples revealed an inverse correlation between C-MYC and patient survival, suggesting that C-MYC expression levels could serve as a prognostic marker for early-stage disease.
['Kfoury|Alain|A|', 'Armaro|Marzia|M|', 'Collodet|Caterina|C|0000-0002-4698-6560', 'Sordet-Dessimoz|Jessica|J|', 'Giner|Maria Pilar|MP|', 'Christen|Stefan|S|', 'Moco|Sofia|S|', 'Leleu|Marion|M|', 'de Leval|Laurence|L|', 'Koch|Ute|U|', 'Trumpp|Andreas|A|', 'Sakamoto|Kei|K|', 'Beermann|Friedrich|F|', 'Radtke|Freddy|F|0000-0003-4315-4045']
D055372:AMP-Activated Protein Kinases D000818:Animals D017209:Apoptosis D045744:Cell Line, Tumor D002470:Cell Survival D002471:Cell Transformation, Neoplastic D019941:Cyclin-Dependent Kinase Inhibitor p16 D020558:GTP Phosphohydrolases D015972:Gene Expression Regulation, Neoplastic D006801:Humans D008544:Melanocytes D008545:Melanoma D008565:Membrane Proteins D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D018384:Oxidative Stress D011379:Prognosis D016271:Proto-Oncogene Proteins c-myc D034622:RNA Interference D034741:RNA, Small Interfering D015398:Signal Transduction
AMPK melanoma oxidative stress c‐Myc gene targeting