<scp>AMPK</scp> β1 reduces tumor progression and improves survival in p53 null mice

Houde, Vanessa P.; Donzelli, Sara; Sacconi, Andrea; Galić, Sandra; Hammill, Joanne A.; Bramson, Jonathan L.; Foster, Robert A.; Tsakiridis, Theodoros; Kemp, Bruce E.; Grasso, Giuseppe; Blandino, Giovanni; Muti, Paola; Steinberg, Gregory R.

doi:10.1002/1878-0261.12079

Cited by 35 publications

(25 citation statements)

References 59 publications

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“…To this end, we generated MEFs from ACC knock-in (KI) mouse model in which AMPK phosphorylation sites on both ACC1 (Ser79) and ACC2 (Ser212) were mutated to alanine ( ACC DKI) ( Fig. 4i ) 29 , 30 . Similar to AMPK deficiency ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Energy-stress-mediated AMPK activation inhibits ferroptosis

et al. 2020

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Energy stress depletes ATP and induces cell death. Here, we identify an unexpected inhibitory role of energy stress on ferroptosis, a form of regulated cell death induced by iron-dependent lipid peroxidation. We found that ferroptotic cell death and lipid peroxidation can be inhibited by treatments that induce or mimic energy stress. Inactivation of AMP-activated protein kinase (AMPK), a sensor of cellular energy status, largely abolishes the protective effects of energy stress on ferroptosis in vitro and on ferroptosis-associated renal ischemia/reperfusion injury in vivo . Cancer cells with high basal AMPK activation are resistant to ferroptosis, and AMPK inactivation sensitizes these cells to ferroptosis. Functional and lipidomic analyses further link AMPK regulation of ferroptosis to AMPK-mediated phosphorylation of acetyl-CoA carboxylase (ACC) and polyunsaturated fatty acid biosynthesis. Together, our study demonstrates that energy stress inhibits ferroptosis partly through AMPK, and reveals an unexpected coupling between ferroptosis and AMPK-mediated energy stress signaling.

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Section: Resultsmentioning

confidence: 99%

“…To generate AMPK α1/α2 WT and DKO MEFs, AMPKα1/α2 L/L LT-MEFs were infected with either empty vector control (pBABE-EV) or Cre-recombinase-expressing retrovirus (pBABE-Cre) and selected with puromycin (2 μg/ml) for four days. Immortalized ACC WT and DKI MEFs were previously described 29 .…”

Section: Methodsmentioning

confidence: 99%

Energy-stress-mediated AMPK activation inhibits ferroptosis

et al. 2020

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“…276 ) and β1 (REF. 277 ) subunits are crossed with MYC-overexpressing mice or p53-null mice, respectively, there is an increase in the appearance of T cell lymphomas and reduced survival. A defining feature of the tumours lacking AMPK was reductions in ACC phosphorylation and an increased rate of de novo lipogenesis.…”

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confidence: 99%

AMP-activated protein kinase: the current landscape for drug development

Steinberg

Carling

2019

Nat Rev Drug Discov

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Since the discovery of AMP-activated protein kinase (AMPK) as a central regulator of energy homeostasis, many exciting insights into its structure, regulation and physiological roles have been revealed. While exercise, caloric restriction, metformin and many natural products increase AMPK activity and exert a multitude of health benefits, developing direct activators of AMPK to elucidate the role of AMPK in these beneficial effects has been challenging. However, in recent years, direct AMPK activators have been identified and tested in preclinical models, and a small number have entered clinical trials. Despite these advances, which disease(s) represent the best indications for therapeutic AMPK activation and the long-term safety of such approaches remain to be established. Commented [WS2]: Au: "The optimal consensus motif of AMPK substrates has been established (BOX 3)" OK?

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“…5′-Adenosine monophosphate-activated protein kinase (AMPK), a heterotrimeric protein complex, is an essential stress and energy sensor [ 78 ]. AMPK consists of alpha (catalytic), beta and gamma (both regulatory) subunits and is activated by numerous kinases through phosphorylation and the increase of calcium in the cytosol through calmodulin-dependent protein kinase kinase beta (CAMKK-ß).…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between the Warburg effect, redox regulation and autophagy induction in tumourigenesis

2018

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Tumourigenic tissue uses modified metabolic signalling pathways in order to support hyperproliferation and survival. Cancer-associated aerobic glycolysis resulting in lactic acid production was described nearly 100 years ago. Furthermore, increased reactive oxygen species (ROS) and lactate quantities increase metabolic, survival and proliferation signalling, resulting in increased tumourigenesis. In order to maintain redox balance, the cell possesses innate antioxidant defence systems such as superoxide dismutase, catalase and glutathione. Several stimuli including cells deprived of nutrients or failure of antioxidant systems result in oxidative stress and cell death induction. Among the cell death machinery is autophagy, a compensatory mechanism whereby energy is produced from damaged and/or redundant organelles and proteins, which prevents the accumulation of waste products, thereby maintaining homeostasis. Furthermore, autophagy is maintained by several pathways including phosphoinositol 3 kinases, the mitogen-activated protein kinase family, hypoxia-inducible factor, avian myelocytomatosis viral oncogene homolog and protein kinase receptor-like endoplasmic reticulum kinase. The persistent potential of cancer metabolism, redox regulation and the crosstalk with autophagy in scientific investigation pertains to its ability to uncover essential aspects of tumourigenic transformation. This may result in clinical translational possibilities to exploit tumourigenic oxidative status and autophagy to advance our capabilities to diagnose, monitor and treat cancer.

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AMPK β1 reduces tumor progression and improves survival in p53 null mice

Cited by 35 publications

References 59 publications

Energy-stress-mediated AMPK activation inhibits ferroptosis

Energy-stress-mediated AMPK activation inhibits ferroptosis

AMP-activated protein kinase: the current landscape for drug development

Crosstalk between the Warburg effect, redox regulation and autophagy induction in tumourigenesis

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