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

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posted on 2016-01-21, 00:00 authored by P.C. Hart, M. Mao, A.L. de Abreu, Kristine Ansenberger-Fricano, D.N. Ekoue, D. Ganini, A. Kajdacsy-Balla
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.

Funding

We are indebted to Drs Larry W. Oberley (in memoriam) and Frederick Domann (University of Iowa) for the generous gift of cell lines stably overexpressing MnSOD, Dr Kevin P. Claffey (University of Connecticut) for the generous gift of MCF-7-AMPKa1 / cells, Dr Kevin Struhl (Harvard University) for the gift of the MCF10A lines expressing v-Src under ER induction, Patricia Mavrogianis, Andrew Hall and Emily Ionetz at the Research Histology Core at the University of Illinois at Chicago for providing histology services, Dr Soumen Bera, Emmanuel Ansong, Paula Green, Alyssa Master and M. Saqib Baig for technical assistance, and for funding provided by the US Department of Defense (ARO no. 61758-LS) to M.G.B, the NCRR/NIH (S10RR027848) to M.G.B., 1R21CA182103-01 to A.M.D. and M.G.B. K.A.-F. and P.C.H. were supported by NIH T32 (HL072742). We also acknowledge gifts from RO1 CA101053 to A.M.D., NIH P01 HL60678 to R.D.M., CAPES—Coordenac¸a˜o de Aperfeic¸oamento Pessoal, Ministe´rio da Cieˆncia e Tecnologia/Brazil—A109/2013 to M.G.B. and M.E.L.C.

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Publisher Statement

This is the copy of an article published in Nature Communications © 2015 Nature Publishing Group. © The Author(s). www.nature.com/naturecommunications

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Nature Publishing Group

issn

ESSN: 2041-1723

Issue date

2015-02-05

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