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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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AMP-Activated Protein Kinases / antagonists & inhibitors
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AMP-Activated Protein Kinases / genetics*
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AMP-Activated Protein Kinases / metabolism
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Breast Neoplasms / enzymology
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Breast Neoplasms / genetics*
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Colonic Neoplasms / enzymology
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Colonic Neoplasms / genetics*
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Colonic Neoplasms / pathology
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Female
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Gene Expression Regulation, Neoplastic*
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Glycolysis / genetics
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Hexokinase / genetics
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Hexokinase / metabolism
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Humans
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Hydrogen Peroxide / metabolism
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Male
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Mitochondria / enzymology
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Mitochondria / genetics
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Neoplasm Staging
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Oxidation-Reduction
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Phosphofructokinase-1 / genetics
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Phosphofructokinase-1 / metabolism
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Prostatic Neoplasms / enzymology
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / pathology
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Pyruvate Kinase / genetics
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Pyruvate Kinase / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Reactive Oxygen Species / metabolism*
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Signal Transduction
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Superoxide Dismutase / antagonists & inhibitors
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Superoxide Dismutase / genetics*
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Superoxide Dismutase / metabolism
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Transcriptional Activation
Substances
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RNA, Small Interfering
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Reactive Oxygen Species
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Hydrogen Peroxide
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Superoxide Dismutase
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Hexokinase
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Phosphofructokinase-1
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Pyruvate Kinase
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AMP-Activated Protein Kinases