Article

AMP-Activated Protein Kinase: A Target for Drugs both Ancient and Modern

Division of Cell Signalling & Immunology, College of Life Sciences, University of Dundee, Dundee, DD1 5EH, Scotland, UK. Electronic address: .
Chemistry & biology (Impact Factor: 6.65). 10/2012; 19(10):1222-36. DOI: 10.1016/j.chembiol.2012.08.019
Source: PubMed

ABSTRACT

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. It is activated, by a mechanism requiring the tumor suppressor LKB1, by metabolic stresses that increase cellular ADP:ATP and/or AMP:ATP ratios. Once activated, it switches on catabolic pathways that generate ATP, while switching off biosynthetic pathways and cell-cycle progress. These effects suggest that AMPK activators might be useful for treatment and/or prevention of type 2 diabetes and cancer. Indeed, AMPK is activated by the drugs metformin and salicylate, the latter being the major breakdown product of aspirin. Metformin is widely used to treat diabetes, while there is epidemiological evidence that both metformin and aspirin provide protection against cancer. We review the mechanisms of AMPK activation by these and other drugs, and by natural products derived from traditional herbal medicines.

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    • "Only one recent study shows that p-AMPK expression was decreased in lamellar tissue of ponies fed a high-carbohydrate diet (Burns et al., 2014). This is of particular relevance to the study of pharmacological interventions in which the drug mode of action is to increase AMPK activity (Yang and Holman, 2006; Hardie et al., 2012). For instance, the mechanism of action of metformin, a biguanide, has been further elucidated to include an ability to activate AMPK (Gundewar et al., 2009). "
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    ABSTRACT: Equine metabolic syndrome is characterized by obesity and insulin resistance (IR). Currently, there is no effective pharmacological treatment for this insidious disease. Glucose uptake is mediated by a family of glucose transporters (GLUT), and is regulated by insulin-dependent and -independent pathways, including 5-AMP-activated protein kinase (AMPK). Importantly, the activation of AMPK, by 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside (AICAR) stimulates glucose uptake in both healthy and diabetic humans. However, whether AICAR promotes glucose uptake in horses has not been established. It is hypothesized that AICAR administration would enhance glucose transport in equine skeletal muscle through AMPK activation. In this study, the effect of an intravenous AICAR infusion on blood glucose and insulin concentrations, as well as on GLUT expression and AMPK activation in equine skeletal muscle (quantified by Western blotting) was examined. Upon administration, plasma AICAR rapidly reached peak concentration. Treatment with AICAR resulted in a decrease (P <0.05) in blood glucose and an increase (P <0.05) in insulin concentration without a change in lactate concentration. The ratio of phosphorylated to total AMPK was increased (P <0.05) in skeletal muscle. While GLUT4 and GLUT1 protein expression remained unchanged, GLUT8 was increased (P <0.05) following AICAR treatment. Up-regulation of GLUT8 protein expression by AICAR suggests that this novel GLUT isoform plays an important role in equine muscle glucose transport. In addition, the data suggest that AMPK activation enhances pancreatic insulin secretion. Collectively, the findings suggest that AICAR acutely promotes muscle glucose uptake in healthy horses and thus its therapeutic potential for managing IR requires investigation. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    • "Imbalances between cell apoptosis and proliferation may lead to peptic ulcer and gastric carcinogenesis [32]. As well as the numerous known metabolic targets of AMPK, it is becoming increasingly clear that AMPK has many other downstream signaling effectors to regulate gene transcription , cell mitosis, cell survival, apoptosis and autophagy [33] [34]. In this study, our data showed that AMPK activation might be a key regulatory step in promoting an anti-apoptotic response in GECs infected with H pylori. Inhibition of AMPK by its kinase inhibitor (Compound C) or targeted shRNAs enhanced cell apoptosis by H pylori, while forced activation of AMPK by its activators (A769662 and resveratrol), or by over-expression of AMPKa1, promoted survival of H pylori-infected GECs. "
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    ABSTRACT: Helicobacter pylori (H pylori), infecting half of the world's population, causes gastritis, duodenal and gastric ulcer, and gastric cancers. AMP-activated protein kinase (AMPK) is a highly conserved regulator of cellular energy and metabolism. Recent studies indicated an important role for AMPK in promoting cell survival. In this study, we discovered that H Pylori induced AMPK activation in transformed (GEC-1 line) and primary human gastric epithelial cells (GECs). Inhibition of H Pylori-stimulated AMPK kinase activity by AMPK inhibitor compound C exacerbated apoptosis in transformed and primary GECs. Meanwhile, downregulation of AMPK expression by targeted shRNAs promoted apoptosis in H pylori-infected GECs. In contrast, A-769662 and resveratrol, two known AMPK activators, or AMPKα1 over-expression, enhanced H Pylori-induced AMPK activation, and inhibited GEC apoptosis. Our data suggested that transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) could be the upstream kinase for AMPK activation by H pylori. Partial depletion of TAK1 by shRNAs not only inhibited AMPK activation, but also suppressed survival of H pylori-infected GECs. Taken together, these results suggest that TAK1-dependent AMPK activation protects GECs from H pylori-Induced apoptosis.
    Preview · Article · Sep 2014 · Biochemical and Biophysical Research Communications
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    • "Binding of AMP to the c subunit, which is antagonized by ATP, activates AMPK by three complementary mechanisms: (i) allosteric activation; (ii) promotion of Thr172 phosphorylation by LKB1; (iii) inhibition of Thr172 dephosphorylation, which can also be triggered by binding of ADP [8] [9] [10] [11] [12]. Cellular stresses that inhibit ATP production or accelerate ATP consumption activate AMPK by causing increases in cellular AMP:ATP and ADP:ATP ratios [8], and AMPK then acts to restore energy homeostasis by switching on catabolic pathways generating ATP, while inhibiting ATP-consuming processes [1] [2] [3]. An alternative upstream activating pathway is triggered by increases in cellular Ca 2+ , causing Thr172 phosphorylation by the calmodulin-dependent protein kinase, CaMKKb [13] [14] [15]. "
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    ABSTRACT: AMPK is known to be activated by oxidative stress. Addition of glucose oxidase to cells generates H2O2 at a constant rate that is opposed by enzymic degradation, providing a good model for physiological oxidative stress. AMPK activation by glucose oxidase correlated with increases in cellular AMP:ATP and was greatly reduced in cells expressing an AMP-insensitive AMPK mutant, although a small degree of activation remained. The effects of increased AMP were partly due to inhibition of Thr172 dephosphorylation. These results suggest that changes in adenine nucleotides, rather than direct oxidative modification, are the major drivers of AMPK activation during oxidative stress.
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