AMPK promotes survival of c‐Myc‐positive melanoma cells by suppressing oxidative stress |
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| Authors: | Caterina Collodet Jessica Sordet‐Dessimoz Maria Pilar Giner Stefan Christen Sofia Moco Marion Leleu Laurence de Leval Ute Koch Andreas Trumpp Kei Sakamoto Friedrich Beermann Freddy Radtke |
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| Affiliation: | 1. Nestlé Institute of Health Sciences SA, Lausanne, Switzerland;2. Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Lausanne, Switzerland;3. Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Swiss Institute for Experimental Cancer Research, Lausanne, Switzerland;4. Institute of Pathology, University Hospital Lausanne, Lausanne, Switzerland;5. Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany;6. Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI‐STEM GmbH), Heidelberg, Germany |
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| 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 NrasQ61KINK4a?/? 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. |
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| Keywords: |
AMPK
c‐Myc gene targeting melanoma oxidative stress |
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