The strange case of AMPK and cancer:Dr Jekyll or Mr Hyde?

The AMP-activated protein kinase (AMPK) acts as a cellular energy sensor. Once switched on by increases in cellular AMP : ATP ratios, it acts to restore energy homeostasis by switching on catabolic pathways while switching off cell growth and proliferation. The canonical AMP-dependent mechanism of activation requires the upstream kinase LKB1, which was identified genetically to be a tumour suppressor. AMPK can also be switched on by increases in intracellular Ca2+, by glucose starvation and by DNA damage via non-canonical, AMP-independent pathways. Genetic studies of the role of AMPK in mouse cancer suggest that, before disease arises, AMPK acts as a tumour suppressor that protects against cancer, with this protection being further enhanced by AMPK activators such as the biguanide phenformin. However, once cancer has occurred, AMPK switches to being a tumour promoter instead, enhancing cancer cell survival by protecting against metabolic, oxidative and genotoxic stresses. Studies of genetic changes in human cancer also suggest diverging roles for genes encoding subunit isoforms, with some being frequently amplified, while others are mutated.</p

AMPK:a nutrient and energy sensor that maintains energy homeostasis

AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor. Once activated by falling energy status, it promotes ATP production by increasing the activity or expression of proteins involved in catabolism while conserving ATP by switching off biosynthetic pathways. AMPK also regulates metabolic energy balance at the whole-body level. For example, it mediates the effects of agents acting on the hypothalamus that promote feeding and entrains circadian rhythms of metabolism and feeding behaviour. Finally, recent studies reveal that AMPK conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability

LKB1 and AMPK and the cancer-metabolism link - ten years after

The identification of a complex containing the tumor suppressor LKB1 as the critical upstream kinase required for the activation of AMP-activated protein kinase (AMPK) by metabolic stress was reported in an article in Journal of Biology in 2003. This finding represented the first clear link between AMPK and cancer. Here we briefly discuss how this discovery came about, and describe some of the insights, especially into the role of AMPK in cancer, that have followed from it. In September 2003, our groups published a joint paper [1] in Journal of Biology (now BMC Biology) that identified the long-sought and elusive upstream kinase acting on AMP-activated protein kinase (AMPK) as a complex containing LKB1, a known tumor suppressor. Similar findings were reported at about the same time by David Carling and Marian Carlson [2] and by Reuben Shaw and Lew Cantley [3]; at the time of writing these three papers have received between them a total of over 2,000 citations. These findings provided a direct link between a protein kinase, AMPK, which at the time was mainly associated with regulation of metabolism, and another protein kinase, LKB1, which was known from genetic studies to be a tumor suppressor. While the idea that cancer is in part a metabolic disorder (first suggested by Warburg in the 1920s [4]) is well recognized today [5], this was not the case in 2003, and our paper perhaps contributed towards its renaissance. The aim of this short review is to recall how we made the original finding, and to discuss some of the directions that these findings have taken the field in the ensuing ten years

Keeping the home fires burning:AMP-activated protein kinase

Living cells obtain energy either by oxidizing reduced compounds of organic or mineral origin or by absorbing light. Whichever energy source is used, some of the energy released is conserved by converting adenosine diphosphate (ADP) to adenosine triphosphate (ATP), which are analogous to the chemicals in a rechargeable battery. The energy released by the conversion of ATP back to ADP is used to drive most energy-requiring processes, including cell growth, cell division, communication and movement. It is clearly essential to life that the production and consumption of ATP are always maintained in balance, and the AMP-activated protein kinase (AMPK) is one of the key cellular regulatory systems that ensures this. In eukaryotic cells (cells with nuclei and other internal membrane-bound structures, including human cells), most ATP is produced in mitochondria, which are thought to have been derived by the engulfment of oxidative bacteria by a host cell not previously able to use molecular oxygen. AMPK is activated by increasing AMP or ADP (AMP being generated from ADP whenever ADP rises) coupled with falling ATP. Relatives of AMPK are found in essentially all eukaryotes, and it may have evolved to allow the host cell to monitor the output of the newly acquired mitochondria and step their ATP production up or down according to the demand. Structural studies have illuminated how AMPK achieves the task of detecting small changes in AMP and ADP, despite the presence of much higher concentrations of ATP. Recently, it has been shown that AMPK can also sense the availability of glucose, the primary carbon source for most eukaryotic cells, via a mechanism independent of changes in AMP or ADP. Once activated by energy imbalance or glucose lack, AMPK modifies many target proteins by transferring phosphate groups to them from ATP. By this means, numerous ATP-producing processes are switched on (including the production of new mitochondria) and ATP-consuming processes are switched off, thus restoring energy homeostasis. Drugs that modulate AMPK have great potential in the treatment of metabolic disorders such as obesity and Type 2 diabetes, and even cancer. Indeed, some existing drugs such as metformin and aspirin, which were derived from traditional herbal remedies, appear to work, in part, by activating AMPK.</p

Accrual of Atherosclerotic Vascular Events in a Multicenter Inception Systemic Lupus Erythematosus Cohort

Objective: In previous studies, atherosclerotic vascular events (AVEs) were shown to occur in ~10% of patients with systemic lupus erythematosus (SLE). We undertook this study to investigate the annual occurrence and potential risk factors for AVEs in a multinational, multiethnic inception cohort of patients with SLE. / Methods: A large 33‐center cohort of SLE patients was followed up yearly between 1999 and 2017. AVEs were attributed to atherosclerosis based on SLE being inactive at the time of the AVE as well as typical atherosclerotic changes observed on imaging or pathology reports and/or evidence of atherosclerosis elsewhere. Analyses included descriptive statistics, rate of AVEs per 1,000 patient‐years, and univariable and multivariable relative risk regression models. / Results: Of the 1,848 patients enrolled in the cohort, 1,710 had ≥1 follow‐up visit after enrollment, for a total of 13,666 patient‐years. Of these 1,710 patients, 3.6% had ≥1 AVEs attributed to atherosclerosis, for an event rate of 4.6 per 1,000 patient‐years. In multivariable analyses, lower AVE rates were associated with antimalarial treatment (hazard ratio [HR] 0.54 [95% confidence interval (95% CI) 0.32–0.91]), while higher AVE rates were associated with any prior vascular event (HR 4.00 [95% CI 1.55–10.30]) and a body mass index of >40 kg/m2 (HR 2.74 [95% CI 1.04–7.18]). A prior AVE increased the risk of subsequent AVEs (HR 5.42 [95% CI 3.17–9.27], P < 0.001). / Conclusion: The prevalence of AVEs and the rate of AVE accrual demonstrated in the present study is much lower than that seen in previously published data. This may be related to better control of both the disease activity and classic risk factors

Understanding the programmatic and contextual forces that influence participation in a government-sponsored international student-mobility program

Although prior research establishes the forces that “push” and “pull” students to participate in foreign study, the transferability of findings from earlier studies is limited by the absence of theoretical grounding. In addition, relatively little is known about how a government-sponsored student mobility program promotes foreign study in a nation with a transitioning economy. Using case study methods, this study explores the characteristics of students who participate in such a program and identifies the programmatic characteristics and contextual forces that promote and limit participation. The findings shed light on the appropriate theoretical perspectives for understanding student participation in a government-sponsored mobility program and illustrate the need to consider how aspects of the national cultural, economic, and political context influence participation. The findings also raise several questions about how an international student mobility program should be structured to encourage participation and maximize benefits to individuals and society within a particular national context

Metabolomics in Early Alzheimer's Disease: Identification of Altered Plasma Sphingolipidome Using Shotgun Lipidomics

The development of plasma biomarkers could facilitate early detection, risk assessment and therapeutic monitoring in Alzheimer's disease (AD). Alterations in ceramides and sphingomyelins have been postulated to play a role in amyloidogensis and inflammatory stress related neuronal apoptosis; however few studies have conducted a comprehensive analysis of the sphingolipidome in AD plasma using analytical platforms with accuracy, sensitivity and reproducibility.We prospectively analyzed plasma from 26 AD patients (mean MMSE 21) and 26 cognitively normal controls in a non-targeted approach using multi-dimensional mass spectrometry-based shotgun lipidomics to determine the levels of over 800 molecular species of lipids. These data were then correlated with diagnosis, apolipoprotein E4 genotype and cognitive performance. Plasma levels of species of sphingolipids were significantly altered in AD. Of the 33 sphingomyelin species tested, 8 molecular species, particularly those containing long aliphatic chains such as 22 and 24 carbon atoms, were significantly lower (p<0.05) in AD compared to controls. Levels of 2 ceramide species (N16:0 and N21:0) were significantly higher in AD (p<0.05) with a similar, but weaker, trend for 5 other species. Ratios of ceramide to sphingomyelin species containing identical fatty acyl chains differed significantly between AD patients and controls. MMSE scores were correlated with altered mass levels of both N20:2 SM and OH-N25:0 ceramides (p<0.004) though lipid abnormalities were observed in mild and moderate AD. Within AD subjects, there were also genotype specific differences.In this prospective study, we used a sensitive multimodality platform to identify and characterize an essentially uniform but opposite pattern of disruption in sphingomyelin and ceramide mass levels in AD plasma. Given the role of brain sphingolipids in neuronal function, our findings provide new insights into the AD sphingolipidome and the potential use of metabolomic signatures as peripheral biomarkers

AMP-Activated Protein Kinase Plays an Important Evolutionary Conserved Role in the Regulation of Glucose Metabolism in Fish Skeletal Muscle Cells

AMPK, a master metabolic switch, mediates the observed increase of glucose uptake in locomotory muscle of mammals during exercise. AMPK is activated by changes in the intracellular AMP∶ATP ratio when ATP consumption is stimulated by contractile activity but also by AICAR and metformin, compounds that increase glucose transport in mammalian muscle cells. However, the possible role of AMPK in the regulation of glucose metabolism in skeletal muscle has not been investigated in other vertebrates, including fish. In this study, we investigated the effects of AMPK activators on glucose uptake, AMPK activity, cell surface levels of trout GLUT4 and expression of GLUT1 and GLUT4 as well as the expression of enzymes regulating glucose disposal and PGC1α in trout myotubes derived from a primary muscle cell culture. We show that AICAR and metformin significantly stimulated glucose uptake (1.6 and 1.3 fold, respectively) and that Compound C completely abrogated the stimulatory effects of the AMPK activators on glucose uptake. The combination of insulin and AMPK activators did not result in additive nor synergistic effects on glucose uptake. Moreover, exposure of trout myotubes to AICAR and metformin resulted in an increase in AMPK activity (3.8 and 3 fold, respectively). We also provide evidence suggesting that stimulation of glucose uptake by AMPK activators in trout myotubes may take place, at least in part, by increasing the cell surface and mRNA levels of trout GLUT4. Finally, AICAR increased the mRNA levels of genes involved in glucose disposal (hexokinase, 6-phosphofructokinase, pyruvate kinase and citrate synthase) and mitochondrial biogenesis (PGC-1α) and did not affect glycogen content or glycogen synthase mRNA levels in trout myotubes. Therefore, we provide evidence, for the first time in non-mammalian vertebrates, suggesting a potentially important role of AMPK in stimulating glucose uptake and utilization in the skeletal muscle of fish