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


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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    • "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.
    Biochemical and Biophysical Research Communications 09/2014; 453(1). DOI:10.1016/j.bbrc.2014.09.028 · 2.30 Impact Factor
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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.
    FEBS Letters 07/2014; 588(18). DOI:10.1016/j.febslet.2014.07.025 · 3.17 Impact Factor
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    • "Moreover, numerous studies have demonstrated that the activation of AMPK leads to increased fatty acid oxidation through phosphorylation of acetyl-CoA carboxylase-2 (ACC2) (Merrill et al., 1997) and glucose uptake in skeletal muscle involving phosphorylation of TBC1D1 (O'Neill et al., 2011; Pehmøller et al., 2009; Sakamoto and Holman, 2008), whereas AMPK signaling to ACC is required for the lipid-lowering and insulin-sensitizing effects of metformin (Fullerton et al., 2013). In line with this, 5-aminoimidazole-4-car- boxamide riboside (AICAR), the most widely used pharmacological AMPK activator, which is converted within cells to the AMP-mimetic AICAR monophosphate (ZMP), improved insulin sensitivity in animal models of insulin resistance (Hardie et al., 2012). However, ZMP modulates other AMP-sensitive enzymes of carbohydrate metabolism, including fructose-1,6-bisphos- phatase in the liver (Vincent et al., 1991) and glycogen phosphorylase in muscle (Longnus et al., 2003). "
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    ABSTRACT: AMPK is a sensor of cellular energy status and a promising target for drugs aimed at metabolic disorders. We have studied the selectivity and mechanism of a recently described activator, C2, and its cell-permeable prodrug, C13. C2 was a potent allosteric activator of α1-complexes that, like AMP, also protected against Thr172 dephosphorylation. Compared with AMP, C2 caused only partial allosteric activation of α2-complexes and failed to protect them against dephosphorylation. We show that both effects could be fully restored by exchanging part of the linker between the autoinhibitory and C-terminal domains in α2, containing the equivalent region from α1 thought to interact with AMP bound in site 3 of the γ subunit. Consistent with our results in cell-free assays, C13 potently inhibited lipid synthesis in hepatocytes from wild-type and was largely ineffective in AMPK-knockout hepatocytes; its effects were more severely affected by knockout of α1 than of α2, β1, or β2.
    Chemistry & Biology 07/2014; 21(7):866-79. DOI:10.1016/j.chembiol.2014.05.014 · 6.65 Impact Factor
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