title: MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer.
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.
authors: 1] Department of Medicine, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA [2] Department of Pathology, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA.
authors: Peter C
authors: PC
authors: Hart
authors: 1] Department of Medicine, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA [2] Department of Pharmacology, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA.
authors: Mao
authors: M
authors: Mao
authors: 1] Department of Medicine, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA [2] Department of Pharmacology, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA [3] Universidade Estadual de Maringa, Avenida Colombo, 5790, CEP, 87020-900 Maringa, PR, Brazil.
authors: Andre Luelsdorf P
authors: AL
authors: de Abreu
authors: 1] Department of Medicine, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA [2] Department of Pharmacology, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA.
authors: Kristine
authors: K
authors: Ansenberger-Fricano
authors: Department of Pathology, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA.
authors: Dede N
authors: DN
authors: Ekoue
authors: Free Radical Metabolite Section, Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences/NIH, 111T.W., Alexander Drive MD-F02, Research Triangle Park, North Carolina 27709, USA.
authors: Douglas
authors: D
authors: Ganini
authors: Department of Pathology, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA.
authors: Andre
authors: A
authors: Kajdacsy-Balla
authors: Department of Pathology, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA.
authors: Alan M
authors: AM
authors: Diamond
authors: 1] Department of Pharmacology, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA [2] Department of Anesthesiology, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA.
authors: Richard D
authors: RD
authors: Minshall
authors: Universidade Estadual de Maringa, Avenida Colombo, 5790, CEP, 87020-900 Maringa, PR, Brazil.
authors: Marcia E L
authors: ME
authors: Consolaro
authors: Department of Physiology and Pharmacology, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, New Jersey 07103, USA.
authors: Janine H
authors: JH
authors: Santos
authors: 1] Department of Medicine, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA [2] Department of Pathology, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA [3] Department of Pharmacology, University of Illinois at Chicago, 909 South Wolcott Avenue, COMRB 1131, Chicago, Illinois 60612, USA.
authors: Marcelo G
authors: MG
authors: Bonini
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000235:genetics; D006593:Hexokinase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D009367:Neoplasm Staging; D010084:Oxidation-Reduction; D010732:Phosphofructokinase-1 / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D006593:Hexokinase; D010732:Phosphofructokinase-1; D011770:Pyruvate Kinase; D055372:AMP-Activated Protein Kinases
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