AMPK promotes survival of c-Myc-positive melanoma cells by suppressing oxidative stress

A. Kfoury; M. Armaro; C. Collodet; J. Sordet-Dessimoz; M.P. Giner; S. Christen; S. Moco; M. Leleu; L. de Leval; U. Koch; A. Trumpp; K. Sakamoto; F. Beermann; F. Radtke

doi:10.15252/embj.201797673

AMPK promotes survival of c-Myc-positive melanoma cells by suppressing oxidative stress

A. Kfoury, M. Armaro, C. Collodet, J. Sordet-Dessimoz, M.P. Giner, S. Christen, S. Moco, M. Leleu, L. de Leval, U. Koch, A. Trumpp, K. Sakamoto, F. Beermann, F. Radtke

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

© 2018 The AuthorsAlthough 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.

Original language	English
Article number	e97673
Journal	EMBO Journal
Volume	37
Issue number	5
DOIs	https://doi.org/10.15252/embj.201797673
Publication status	Published - 1 Mar 2018
Externally published	Yes

Funding

This work was in part supported by the Swiss National Science Foundation and the Swiss Cancer League to F.R. We would like to acknowledge Christelle Dubey, Laure Bardouillet, Pasqualina Magliano, and Marianne Nkosi for technical assistance, Lionel Larue for providing the Tyr::Cre. We would like to thank Aleksandra Radenovic, Jose Artacho, the histology team, and Sintia Winkler for technical assistance with microscopy, histology, and flow cytometry. We would like to thank Gisele Ferrand for guidance and advice concerning animal experiments as well as the DNA array facility of the University of Lausanne for RNA sequencing and technical analysis.

Funders	Funder number
Swiss Cancer League
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Krebsliga Schweiz

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@article{7676402f91044e54b5410196b2b29679,

title = "AMPK promotes survival of c-Myc-positive melanoma cells by suppressing oxidative stress",

abstract = "{\textcopyright} 2018 The AuthorsAlthough 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.",

author = "A. Kfoury and M. Armaro and C. Collodet and J. Sordet-Dessimoz and M.P. Giner and S. Christen and S. Moco and M. Leleu and {de Leval}, L. and U. Koch and A. Trumpp and K. Sakamoto and F. Beermann and F. Radtke",

year = "2018",

month = mar,

day = "1",

doi = "10.15252/embj.201797673",

language = "English",

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T1 - AMPK promotes survival of c-Myc-positive melanoma cells by suppressing oxidative stress

AU - Kfoury, A.

AU - Armaro, M.

AU - Collodet, C.

AU - Sordet-Dessimoz, J.

AU - Giner, M.P.

AU - Christen, S.

AU - Moco, S.

AU - Leleu, M.

AU - de Leval, L.

AU - Koch, U.

AU - Trumpp, A.

AU - Sakamoto, K.

AU - Beermann, F.

AU - Radtke, F.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - © 2018 The AuthorsAlthough 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.

AB - © 2018 The AuthorsAlthough 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.

U2 - 10.15252/embj.201797673

DO - 10.15252/embj.201797673

M3 - Article

SN - 0261-4189

VL - 37

JO - EMBO Journal

JF - EMBO Journal

IS - 5

M1 - e97673

ER -

AMPK promotes survival of c-Myc-positive melanoma cells by suppressing oxidative stress

Abstract

Funding

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