MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer

Peter C. Hart, Mao Mao, Andre Luelsdorf P. de Abreu, Kristine Ansenberger-Fricano, Dede N. Ekoue, Douglas Ganini, Andre Kajdacsy-Balla, Alan M. Diamond, Richard D. Minshall, Marcia E. L. Consolaro, Janine H. Santos and Marcelo G. Bonini ()
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Peter C. Hart: University of Illinois at Chicago
Mao Mao: University of Illinois at Chicago
Andre Luelsdorf P. de Abreu: University of Illinois at Chicago
Kristine Ansenberger-Fricano: University of Illinois at Chicago
Dede N. Ekoue: University of Illinois at Chicago
Douglas Ganini: Free Radical Metabolite Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences/NIH
Andre Kajdacsy-Balla: University of Illinois at Chicago
Alan M. Diamond: University of Illinois at Chicago
Richard D. Minshall: University of Illinois at Chicago
Marcia E. L. Consolaro: Universidade Estadual de Maringa
Janine H. Santos: University of Medicine and Dentistry of New Jersey
Marcelo G. Bonini: University of Illinois at Chicago

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract Manganese superoxide dismutase (MnSOD/SOD2) is a mitochondria-resident enzyme that governs the types of reactive oxygen species egressing from the organelle to affect cellular signalling. Here we demonstrate that MnSOD upregulation in cancer cells establishes a steady flow of H2O2 originating from mitochondria that sustains AMP-activated kinase (AMPK) activation and the metabolic shift to glycolysis. Restricting MnSOD expression or inhibiting AMPK suppresses the metabolic switch and dampens the viability of transformed cells indicating that the MnSOD/AMPK axis is critical to support cancer cell bioenergetics. Recapitulating in vitro findings, clinical and epidemiologic analyses of MnSOD expression and AMPK activation indicated that the MnSOD/AMPK pathway is most active in advanced stage and aggressive breast cancer subtypes. Taken together, our results indicate that MnSOD serves as a biomarker of cancer progression and acts as critical regulator of tumour cell metabolism.

Date: 2015
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DOI: 10.1038/ncomms7053

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