MnSOD upregulation sustains the Warburg effect via mitochondrial ROS and AMPK-dependent signalling in cancer. Nat Commun 2015 Feb 05;6:6053
Date
02/06/2015Pubmed ID
25651975Pubmed Central ID
PMC4319569DOI
10.1038/ncomms7053Scopus ID
2-s2.0-84923169953 (requires institutional sign-in at Scopus site) 195 CitationsAbstract
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.
Author List
Hart PC, Mao M, de Abreu AL, Ansenberger-Fricano K, Ekoue DN, Ganini D, Kajdacsy-Balla A, Diamond AM, Minshall RD, Consolaro ME, Santos JH, Bonini MGMESH terms used to index this publication - Major topics in bold
AMP-Activated Protein KinasesBreast Neoplasms
Cell Line, Tumor
Colonic Neoplasms
Female
Gene Expression Regulation, Neoplastic
Glycolysis
Hexokinase
Humans
Hydrogen Peroxide
Male
Mitochondria
Neoplasm Staging
Oxidation-Reduction
Phosphofructokinase-1
Prostatic Neoplasms
Pyruvate Kinase
RNA, Small Interfering
Reactive Oxygen Species
Signal Transduction
Superoxide Dismutase
Transcriptional Activation