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MnSOD/SOD2 upregulation sustains the Warburg effect via mitochondrial ROS and AMPK‐dependent signaling in cancer
Author(s) -
Hart Peter,
Mao Mao,
Abreu Andre,
Fricano Kristine,
Ekoue Dede,
Minshall Richard,
Diamond Alan,
Bonini Marcelo
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.884.62
Subject(s) - ampk , sod2 , warburg effect , cancer cell , microbiology and biotechnology , downregulation and upregulation , mitochondrion , viability assay , bioenergetics , autophagy , glycolysis , chemistry , cancer research , signal transduction , superoxide dismutase , protein kinase a , biology , apoptosis , kinase , cancer , oxidative stress , biochemistry , metabolism , genetics , gene
Manganese superoxide dismutase (MnSOD/SOD2) is a mitochondria‐resident enzyme governing rates and types of reactive oxygen species egressing from the organelle to affect signaling at the cellular level. We show MnSOD upregulation in cancer cells establishes a steady flow of H 2 O 2 originating from mitochondria that sustains AMP‐activated kinase (AMPK) activation and the metabolic switch to glycolysis by cancer cells. AMPK is an energetic sensor/ regulator of the cellular metabolism, is activated by a reduction in the intracellular ratio ATP/AMP and as shown by our studies activates glycolysis in cancer. Restricting MnSOD expression or inhibiting AMPK suppressed the metabolic switch and dampened the viability of transformed cells indicating that the MnSOD/AMPK axis is central for the induction of the Warburg effect, cell proliferation, and tumor survival. The analysis of MnSOD expression and AMPK activation in clinical cancer samples recapitulated in vitro findings by demonstrating that the MnSOD/AMPK pathway is most active in advanced stage and aggressive breast cancer subtypes. Taken together our studies indicate that the MnSOD/AMPK axis is central to maintain aggressive cancer cell viability and its inhibition may be of potential utility to target progressing tumors.