AMPK regulates metabolism and survival in response to ionizing radiation

Zannella, Vanessa E.; Cojocari, Dan; Hilgendorf, Susan; Vellanki, Ravi N.; Chung, Stephen W.; Wouters, Bradly G.; Koritzinsky, Marianne

doi:10.1016/j.radonc.2011.05.049

Cited by 57 publications

(51 citation statements)

References 35 publications

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“…Although AMPK is primarily a responder to low fuel, [36][37][38] it is also a wider stress-activated kinase, being also activated by oxidative stress, osmotic stress, 39 ionizing radiation, 40 and hypoxia, 41 and may therefore play a role in signaling akin to classical stress-activated protein kinases such as p38MAPK and jun N-terminal kinase. We suggest that the metabolic stress of erythophagocytosis parallels that of energy deprivation because both are associated with oxidative stress and require activation of catabolic pathways.…”

Section: Ampk and Metabolic Stressmentioning

confidence: 99%

5′-AMP–Activated Protein Kinase–Activating Transcription Factor 1 Cascade Modulates Human Monocyte–Derived Macrophages to Atheroprotective Functions in Response to Heme or Metformin

Wan

Huo

Johns

et al. 2013

ATVB

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Objective— Intraplaque hemorrhage (IPH) is an important driver of the progression of atherosclerotic plaques. Recently, we characterized Mhem as a novel macrophage phenotype that limits the atherogenicity of IPH. Mhem are directed by activating transcription factor 1 (ATF1), which is activated by phosphorylation. A better understanding of the counteratherogenic ATF1–Mhem pathway may facilitate antiatherosclerotic therapies. Approach and Results— We tested the hypothesis that heme in pathologically relevant concentrations activates the ATF1–Mhem pathway via 5′-AMP–activated protein kinase (AMPK) in primary human monocyte–derived macrophages and mouse bone marrow macrophages. We found that heme (10 μmol/L) activates AMPK, and downstream ATF1-mediated coinduction of heme oxygenase and liver X receptor that characterize Mhem. Heme increased macrophage phospho-AMPK, phospho-ATF1, and its target genes, and these effects were inhibited by the AMPK antagonist dorsomorphin, or by AMPK-knockdown with small inhibitory ribonucleic acid. The AMPK-activating oral hypoglycemic agent metformin also induced and phosphorylated ATF1 at a clinically relevant concentration (10 μmol/L). Functional effects of heme and metformin were inhibited by AMPK-knockdown and included suppression of macrophage oxidative stress; increased cholesterol export; protection from foam-cell formation; and suppression of macrophage inflammatory activation (human leukocyte antigen type DR expression). Conclusions— Our data indicate that heme activates the ATF1 pathway in human macrophages via AMPK, and that a similar response occurs after treatment of cells with metformin. Our results suggest an in vitro mechanism that may explain the clinical evidence that metformin has vascular protective effects beyond its role in treating hyperglycemia.

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Section: Ampk and Metabolic Stressmentioning

confidence: 99%

5′-AMP–Activated Protein Kinase–Activating Transcription Factor 1 Cascade Modulates Human Monocyte–Derived Macrophages to Atheroprotective Functions in Response to Heme or Metformin

Wan

Huo

Johns

et al. 2013

ATVB

View full text Add to dashboard Cite

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“…11, 24 To study the role of AMPK in radiation-induced senescence, the activity of AMPK in irradiated MDA-MB-231-2A and MCF-7 cells was examined via analysis of Thr-172 phosphorylation. As shown in Figure 2a and Supplementary Figure S4C, radiation induced sustained AMPK phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

Radiation induces senescence and a bystander effect through metabolic alterations

et al. 2014

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Cellular senescence is a state of irreversible growth arrest; however, the metabolic processes of senescent cells remain active. Our previous studies have shown that radiation induces senescence of human breast cancer cells that display low expression of securin, a protein involved in control of the metaphase–anaphase transition and anaphase onset. In this study, the protein expression profile of senescent cells was resolved by two-dimensional gel electrophoresis to investigate associated metabolic alterations. We found that radiation induced the expression and activation of glyceraldehyde-3-phosphate dehydrogenase that has an important role in glycolysis. The activity of lactate dehydrogenase A, which is involved in the conversion of pyruvate to lactate, the release of lactate and the acidification of the extracellular environment, was also induced. Inhibition of glycolysis by dichloroacetate attenuated radiation-induced senescence. In addition, radiation also induced activation of the 5′-adenosine monophosphate-activated protein kinase (AMPK) and nuclear factor kappa B (NF-κB) pathways to promote senescence. We also found that radiation increased the expression of monocarboxylate transporter 1 (MCT1) that facilitates the export of lactate into the extracellular environment. Inhibition of glycolysis or the AMPK/NF-κB signalling pathways reduced MCT1 expression and rescued the acidification of the extracellular environment. Interestingly, these metabolic-altering signalling pathways were also involved in radiation-induced invasion of the surrounding, non-irradiated breast cancer and normal endothelial cells. Taken together, radiation can induce the senescence of human breast cancer cells through metabolic alterations.

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“…In prostate cancer, our study group analysis suggests that the beneficial effects of metformin use could be limited to those undergoing radical radiotherapy. The AMPK pathway is known to play a role in regulating cellular responses to radiotherapy, [70] and studies in xenograft mice models suggest that metformin can improve tumour oxygenation and therefore radiation response [71]. …”

Section: Discussionmentioning

confidence: 99%

Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis

et al. 2016

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AMPK regulates metabolism and survival in response to ionizing radiation

Cited by 57 publications

References 35 publications

5′-AMP–Activated Protein Kinase–Activating Transcription Factor 1 Cascade Modulates Human Monocyte–Derived Macrophages to Atheroprotective Functions in Response to Heme or Metformin

5′-AMP–Activated Protein Kinase–Activating Transcription Factor 1 Cascade Modulates Human Monocyte–Derived Macrophages to Atheroprotective Functions in Response to Heme or Metformin

Radiation induces senescence and a bystander effect through metabolic alterations

Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis

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