scholarly journals AMP-Activated Protein Kinase: Do We Need Activators or Inhibitors to Treat or Prevent Cancer?

2020 ◽  
Vol 22 (1) ◽  
pp. 186
Author(s):  
Fiona M. Russell ◽  
David Grahame Hardie
Keyword(s):  
Protein Kinase ◽  
Genome Stability ◽  
Metabolic Disorders ◽  
Metabolic Stress ◽  
Cellular Energy ◽  
Downstream Effector ◽  
Wide Range ◽  
Cell Growth And Proliferation ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is a key regulator of cellular energy balance. In response to metabolic stress, it acts to redress energy imbalance through promotion of ATP-generating catabolic processes and inhibition of ATP-consuming processes, including cell growth and proliferation. While findings that AMPK was a downstream effector of the tumour suppressor LKB1 indicated that it might act to repress tumourigenesis, more recent evidence suggests that AMPK can either suppress or promote cancer, depending on the context. Prior to tumourigenesis AMPK may indeed restrain aberrant growth, but once a cancer has arisen, AMPK may instead support survival of the cancer cells by adjusting their rate of growth to match their energy supply, as well as promoting genome stability. The two isoforms of the AMPK catalytic subunit may have distinct functions in human cancers, with the AMPK-α1 gene often being amplified, while the AMPK-α2 gene is more often mutated. The prevalence of metabolic disorders, such as obesity and Type 2 diabetes, has led to the development of a wide range of AMPK-activating drugs. While these might be useful as preventative therapeutics in individuals predisposed to cancer, it seems more likely that AMPK inhibitors, whose development has lagged behind that of activators, would be efficacious for the treatment of pre-existing cancers.

AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer

2011 ◽  
Vol 39 (1) ◽  
pp. 1-13 ◽  
Author(s):  
D. Grahame Hardie
Keyword(s):  
Protein Kinase ◽  
Metabolic Disorders ◽  
Adenine Nucleotides ◽  
Metabolic Stress ◽  
Branch Points ◽  
Atp Production ◽  
Nucleotide Binding Sites ◽  
Anticancer Effects ◽  
Energy Sensor ◽  
Amp Activated Protein Kinase

It is essential to life that a balance is maintained between processes that produce ATP and those that consume it. An obvious way to do this would be to have systems that monitor the levels of ATP and ADP, although because of the adenylate kinase reaction (2ADP↔ATP+AMP), AMP is actually a more sensitive indicator of energy stress than ADP. Following the discoveries that glycogen phosphorylase and phosphofructokinase were regulated by AMP and ATP, Daniel Atkinson proposed that all enzymes at branch points between biosynthesis and degradation would be regulated by adenine nucleotides. This turned out to be correct, but what Atkinson did not anticipate was that sensing of nucleotides would, in most cases, be performed not by the metabolic enzymes themselves, but by a signalling protein, AMPK (AMP-activated protein kinase). AMPK occurs in essentially all eukaryotes and consists of heterotrimeric complexes comprising catalytic α subunits and regulatory β and γ subunits, of which the latter carries the nucleotide-binding sites. Once activated by a metabolic stress, it phosphorylates numerous targets that alter enzyme activity and gene expression to initiate corrective responses. In lower eukaryotes, it is critically involved in the responses to starvation for a carbon source. Because of its ability to switch cellular metabolism from anabolic to catabolic mode, AMPK has become a key drug target to combat metabolic disorders associated with overnutrition such as Type 2 diabetes, and some existing anti-diabetic drugs (e.g. metformin) and many ‘nutraceuticals’ work by activating AMPK, usually via inhibition of mitochondrial ATP production. AMPK activators also potentially have anticancer effects, and there is already evidence that metformin provides protection against the initiation of cancer. Whether AMPK activators can be used to treat existing cancer is less clear, because many tumour cells appear to have been selected for mutations that inactivate the AMPK system. However, if we can identify the various mechanisms by which this occurs, we may be able to find ways of overcoming it.

Identification and characterization of a novel sucrose-non-fermenting protein kinase/AMP-activated protein kinase-related protein kinase, SNARK

2001 ◽  
Vol 355 (2) ◽  
pp. 297-305 ◽  
Author(s):  
Diana L. LEFEBVRE ◽  
Yahong BAI ◽  
Nazanin SHAHMOLKY ◽  
Monika SHARMA ◽  
Raymond POON ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cellular Response ◽  
Catalytic Domain ◽  
Metabolic Stress ◽  
Glucose Deprivation ◽  
Protein Band ◽  
Northern Blotting ◽  
Significant Similarity ◽  
Amp Activated Protein Kinase

Subtraction hybridization after the exposure of keratinocytes to ultraviolet radiation identified a differentially expressed cDNA that encodes a protein of 630 amino acid residues possessing significant similarity to the catalytic domain of the sucrose-non-fermenting protein kinase (SNF1)/AMP-activated protein kinase (AMPK) family of serine/threonine protein kinases. Northern blotting and reverse-transcriptase-mediated PCR demonstrated that mRNA transcripts for the SNF1/AMPK-related kinase (SNARK) were widely expressed in rodent tissues. The SNARK gene was localized to human chromosome 1q32 by fluorescent in situ hybridization. SNARK was translated in vitro to yield a single protein band of approx. 76kDa; Western analysis of transfected baby hamster kidney (BHK) cells detected two SNARK-immunoreactive bands of approx. 76-80kDa. SNARK was capable of autophosphorylation in vitro; immunoprecipitated SNARK exhibited phosphotransferase activity with the synthetic peptide substrate HMRSAMSGLHLVKRR (SAMS) as a kinase substrate. SNARK activity was significantly increased by AMP and 5-amino-4-imidazolecarboxamide riboside (AICAriboside) in rat keratinocyte cells, implying that SNARK might be activated by an AMPK kinase-dependent pathway. Furthermore, glucose deprivation increased SNARK activity 3-fold in BHK fibroblasts. These findings identify SNARK as a glucose- and AICAriboside-regulated member of the AMPK-related gene family that represents a new candidate mediator of the cellular response to metabolic stress.

AMP-Activated Protein Kinase: A Metabolic Stress Sensor in the Heart

2015 ◽  
pp. 187-225
Author(s):  
Martin Pelosse ◽  
Malgorzata Tokarska-Schlattner ◽  
Uwe Schlattner
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Metabolic Stress ◽  
Stress Sensor ◽  
Amp Activated Protein Kinase ◽  
Kinase A

scholarly journals Angiotensin AT1 receptor antagonism by losartan stimulates adipocyte browning via induction of apelin

2020 ◽  
Vol 295 (44) ◽  
pp. 14878-14892
Author(s):  
Dong Young Kim ◽  
Mi Jin Choi ◽  
Tae Kyung Ko ◽  
Na Hyun Lee ◽  
Ok-Hee Kim ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Protein Kinase ◽  
Metabolic Disorders ◽  
Angiotensin Ii Receptor ◽  
Adeno Associated Virus ◽  
Receptor Antagonism ◽  
White Adipocytes ◽  
Treatment Of Obesity ◽  
Amp Activated Protein Kinase

Adipocyte browning appears to be a potential therapeutic strategy to combat obesity and related metabolic disorders. Recent studies have shown that apelin, an adipokine, stimulates adipocyte browning and has negative cross-talk with angiotensin II receptor type 1 (AT1 receptor) signaling. Here, we report that losartan, a selective AT1 receptor antagonist, induces browning, as evidenced by an increase in browning marker expression, mitochondrial biogenesis, and oxygen consumption in murine adipocytes. In parallel, losartan up-regulated apelin expression, concomitant with increased phosphorylation of protein kinase B and AMP-activated protein kinase. However, the siRNA-mediated knockdown of apelin expression attenuated losartan-induced browning. Angiotensin II cotreatment also inhibited losartan-induced browning, suggesting that AT1 receptor antagonism-induced activation of apelin signaling may be responsible for adipocyte browning induced by losartan. The in vivo browning effects of losartan were confirmed using both C57BL/6J and ob/ob mice. Furthermore, in vivo apelin knockdown by adeno-associated virus carrying–apelin shRNA significantly inhibited losartan-induced adipocyte browning. In summary, these data suggested that AT1 receptor antagonism by losartan promotes the browning of white adipocytes via the induction of apelin expression. Therefore, apelin modulation may be an effective strategy for the treatment of obesity and its related metabolic disorders.

AMP-activated protein kinase: new regulation, new roles?

2012 ◽  
Vol 445 (1) ◽  
pp. 11-27 ◽  
Author(s):  
David Carling ◽  
Claire Thornton ◽  
Angela Woods ◽  
Matthew J. Sanders
Keyword(s):  
Protein Kinase ◽  
Living Cells ◽  
Cellular Functions ◽  
Disease States ◽  
Kinase Cascade ◽  
Amp Activated Protein Kinase ◽  
Obesity And Cancer ◽  
Hydrolysis Of ◽  
Protein Kinase Cascade

The hydrolysis of ATP drives virtually all of the energy-requiring processes in living cells. A prerequisite of living cells is that the concentration of ATP needs to be maintained at sufficiently high levels to sustain essential cellular functions. In eukaryotic cells, the AMPK (AMP-activated protein kinase) cascade is one of the systems that have evolved to ensure that energy homoeostasis is maintained. AMPK is activated in response to a fall in ATP, and recent studies have suggested that ADP plays an important role in regulating AMPK. Once activated, AMPK phosphorylates a broad range of downstream targets, resulting in the overall effect of increasing ATP-producing pathways whilst decreasing ATP-utilizing pathways. Disturbances in energy homoeostasis underlie a number of disease states in humans, e.g. Type 2 diabetes, obesity and cancer. Reflecting its key role in energy metabolism, AMPK has emerged as a potential therapeutic target. In the present review we examine the recent progress aimed at understanding the regulation of AMPK and discuss some of the latest developments that have emerged in key areas of human physiology where AMPK is thought to play an important role.

scholarly journals Anti-diabetic effect of Oyster Mushroom mediates through increased AMP-activated protein kinase (AMPK) and cyclic AMP-response element binding (CREB) protein in Type 2 Diabetic model Rats

2018 ◽  
Vol 17 (4) ◽  
pp. 661-668
Author(s):  
Manoj Mandal ◽  
Rakibuzzaman ◽  
Begum Rokeya ◽  
Liaquat Ali ◽  
Zahid Hassan ◽  
...  
Keyword(s):  
Body Weight ◽  
Protein Kinase ◽  
Fasting Glucose ◽  
Treated Group ◽  
Diabetic Control ◽  
Diabetic Rats ◽  
Oyster Mushroom ◽  
Diabetic Model ◽  
Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) and c-AMP-response element binding protein (CREB) are found to be important proteins in metabolic system. AMPK has become the focus as a novel therapeutic target for the treatment of metabolic syndromes. Oyster mushroom is traditionally used as remedy of diabetes and hypertension. The present study aims to observe the stimulation of AMPK and CREB in streptozotocin-induced diabetic model rats through Oyster mushroom administration. Long Evan’s rats were used to create type 2 model diabetic rats through intraperitoneal injection of streptozotocin at 90mg/kg body weight of 48hr old pups. Rats were divided into three groups: diabetic control rats, glibenclamide treated diabetic rats (positive control) and mushroom treated diabetic rats (experimental group). Mushroom was administered orally at a dose of 1.25g/kg body weight in semisolid forms. After five weeks rats were sacrificed, serum and tissues were collected for future analysis. Glucose was measured using glucose-oxidase method, lipid profile by enzymaticcolorimetric method. Proteins from different tissues were extracted using RIPA cell lysis buffer, AMPK and CREB were identified using western blot and immuno-precipitation techniques. A significant decreased of fasting glucose was found after 35 days of experiment when it compared with control diabetic rats (M ± SD, mmol/l, Diabetic control group: 8.0±1.1; Mushroom treated diabetic group: 6.4±1.0; p=0.021). Glibenclamide treated diabetic rats have also shown decreased fasting glucose compared to control diabetic rats. In paired ‘t’ test analysis, it has been found that serum fasting glucose level was significantly decreased on 35th day compared the 0 day in both mushroom treated group (p=0.027) and in glibenclamide treated group (p=0.005). Serum TG level was decreased on 35th day compared to 0day in mushroom treated diabetic model rats only (M±SD, mg/dl, 0 day: 84±13; 35th day: 61±6, p=0.002). No significant changes of cholesterol, HDL and LDL were noticed in the experimental groups following treatment with mushroom. Western blot analyses have shown increased band intensity of AMPK and p-CREB in mushroom treated diabetic model rats. Therefore, it can be concluded that Anti-hyperglycemic property of Oyster mushroom could be explained through increased expression of AMPK and activation of CREB.Bangladesh Journal of Medical Science Vol.17(4) 2018 p.661-668

scholarly journals Metabolic Stress Modulates Motor Patterning via AMP-Activated Protein Kinase

2011 ◽  
Vol 31 (9) ◽  
pp. 3207-3216 ◽  
Author(s):  
C. I. Rodgers-Garlick ◽  
G. A. B. Armstrong ◽  
R. M. Robertson
Keyword(s):  
Protein Kinase ◽  
Metabolic Stress ◽  
Amp Activated Protein Kinase

5′-AMP-activated protein kinase is inactivated by adrenergic signalling in adult cardiac myocytes

2011 ◽  
Vol 32 (2) ◽  
pp. 197-209 ◽  
Author(s):  
Yugo Tsuchiya ◽  
Fiona C. Denison ◽  
Richard B. Heath ◽  
David Carling ◽  
David Saggerson
Keyword(s):  
Protein Kinase ◽  
Cardiac Myocytes ◽  
Calcium Signalling ◽  
Metabolic Stress ◽  
Protein Kinase Activity ◽  
Adult Rat ◽  
Protein Kinase C Inhibitor ◽  
Amp Activated Protein Kinase

In adult rat cardiac myocytes adrenaline decreased AMPK (AMP-activated protein kinase) activity with a half-time of approximately 4 min, decreased phosphorylation of AMPK (α-Thr172) and decreased phosphorylation of ACC (acetyl-CoA carboxylase). Inactivation of AMPK by adrenaline was through both α1- and β-ARs (adrenergic receptors), but did not involve cAMP or calcium signalling, was not blocked by the PKC (protein kinase C) inhibitor BIM I (bisindoylmaleimide I), by the ERK (extracellular-signal-regulated kinase) cascade inhibitor U0126 or by PTX (pertussis toxin). Adrenaline caused no measurable change in LKB1 activity. Adrenaline decreased AMPK activity through a process that was distinct from AMPK inactivation in response to insulin or PMA. Neither adrenaline nor PMA altered the myocyte AMP:ATP ratio although the adrenaline effect was attenuated by oligomycin and by AICAR (5-amino-4-imidazolecarboxamide-1-β-D-ribofuranoside), agents that mimic ‘metabolic stress’. Inactivation of AMPK by adrenaline was abolished by 1 μM okadaic acid suggesting that activation of PP2A (phosphoprotein phosphatase 2A) might mediate the adrenaline effect. However, no change in PP2A activity was detected in myocyte extracts. Adrenaline increased phosphorylation of the AMPK β-subunit in vitro but there was no detectable change in vivo in phosphorylation of previously identified AMPK sites (β-Ser24, β-Ser108 or β-Ser182) suggesting that another site(s) is targeted.

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