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AMPK promotes survival of c‐Myc‐positive melanoma cells by suppressing oxidative stress
Author(s) -
Kfoury Alain,
Armaro Marzia,
Collodet Caterina,
SordetDessimoz Jessica,
Giner Maria Pilar,
Christen Stefan,
Moco Sofia,
Leleu Marion,
Leval Laurence,
Koch Ute,
Trumpp Andreas,
Sakamoto Kei,
Beermann Friedrich,
Radtke Freddy
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201797673
Subject(s) - biology , oxidative stress , ampk , cancer research , melanoma , oxidative phosphorylation , microbiology and biotechnology , protein kinase a , phosphorylation , biochemistry
Abstract 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 Nras Q61K INK4a −/− 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.