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 signaling. 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 suppress the metabolic switch and dampens the viability of transformed cells indicating that the MnSOD/AMPK axis is critical in 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 tumor cell metabolism.

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

“…We confirmed by quantitative PCR that splicing of Camk2b was altered in muscle from HSA LR mice (exon 13 exclusion; Supplemental Figure 1B), while overall expression of Camk2 transcripts was unchanged in comparison with controls (Supplemental Figure 1C). As CaMKII regulates AMPK (24)(25)(26), these results suggest that impaired AMPK activation in HSA LR muscle may rely on mis-splicing-dependent CaMKII deficiency.…”

“…Although we have not studied the upstream mechanisms involved in this deregulation, mis-splicing-dependent CaMKII deficiency could well account for the limited AMPK activation in DM1 muscle (21,(23)(24)(25)(26). Interestingly, Jones et al recently reported increased GSK3β levels and activity in HSA LR muscle (45), which may also contribute to the perturbation of AMPK in DM1 muscle (46).…”

Rasfonin promotes autophagy and apoptosis via upregulation of reactive oxygen species (ROS)/JNK pathway

“…Cancer cells produce higher levels of ROS than normal cells, and this leads to cancer progression (Hart et al 2015). ROS are important signalling molecules that mediate many signal transduction pathways and benefit for cellular survival (Focaccetti et al 2015); however, the overproduction of ROS damage cell by activation of apoptosis or necrosis.…”

Oxidized CaMKII promotes asthma through the activation of mast cells

“…CaMKII is held in an inactive state but can be activated by oxidization at methionines 281/282 in the CaMKII regulatory domain in the presence of ROS (12,13), locking the oxidized CaMKII (ox-CaMKII) into a persistently active configuration. Both NADPH oxidase (12)(13)(14) and mitochondria (15,16) are considered as major sources of ROS for ox-CaMKII (12). Ox-CaMKII has been linked with various diseases, including vascular disease (14,17), diabetes (15), asthma (18), and cancer (16), and has been shown to promote inflammatory signaling (19), cell proliferation (20), and ion channel activity (21).…”

“…Both NADPH oxidase (12)(13)(14) and mitochondria (15,16) are considered as major sources of ROS for ox-CaMKII (12). Ox-CaMKII has been linked with various diseases, including vascular disease (14,17), diabetes (15), asthma (18), and cancer (16), and has been shown to promote inflammatory signaling (19), cell proliferation (20), and ion channel activity (21). Interestingly, increased expression of ox-CaMKII has been observed in the airway epithelium of asthmatic patients, which was correlated with the severity of asthma (18).…”