An Oncogenic Role for the Ubiquitin Ligase UBE2O by Targeting AMPK-α2 for Degradation

There has been controversy regarding the role of AMPK in cancer, some of which may be due to functional differences between isoforms. In this issue of Cancer Cell, Vila et al. report that UBE2O, a ubiquitin ligase overexpressed in some human cancers, specifically triggers the ubiquitination and degradation of AMPK-α2.</p

AMP-activated protein kinase:a key regulator of energy balance with many roles in human disease

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that regulates cellular and whole-body energy balance. A recently reported crystal structure has illuminated the complex regulatory mechanisms by which AMP and ADP cause activation of AMPK, involving phosphorylation by the upstream kinase LKB1. Once activated by falling cellular energy status, AMPK activates catabolic pathways that generate ATP whilst inhibiting anabolic pathways and other cellular processes that consume ATP. A role of AMPK is implicated in many human diseases. Mutations in the ?2 subunit cause heart disease due to excessive glycogen storage in cardiac myocytes, leading to ventricular pre-excitation. AMPK-activating drugs reverse many of the metabolic defects associated with insulin resistance, and recent findings suggest that the insulin-sensitizing effects of the widely used antidiabetic drug metformin are mediated by AMPK. The upstream kinase LKB1 is a tumour suppressor, and AMPK may exert many of its antitumour effects. AMPK activation promotes the oxidative metabolism typical of quiescent cells, rather than the aerobic glycolysis observed in tumour cells and cells involved in inflammation, explaining in part why AMPK activators have both antitumour and anti-inflammatory effects. Salicylate (the major in vivo metabolite of aspirin) activates AMPK, and this could be responsible for at least some of the anticancer and anti-inflammatory effects of aspirin. In addition to metformin and salicylates, novel drugs that modulate AMPK are likely to enter clinical trials soon. Finally, AMPK may be involved in viral infection: downregulation of AMPK during hepatitis C virus infection appears to be essential for efficient viral replication.</p

Molecular pathways:is AMPK a friend or a foe in cancer?

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status expressed in essentially all eukaryotic cells. Once activated by energetic stress via a mechanism that detects increases in AMP:ATP and ADP:ATP ratios, AMPK acts to restore energy homeostasis by switching on catabolic pathways that generate ATP, while switching off ATP-consuming processes, including anabolic pathways required for cell growth and proliferation. AMPK activation promotes the glucose-sparing, oxidative metabolism utilized by most quiescent cells, rather than the rapid glucose uptake and glycolysis used by most proliferating cells. Numerous pharmacological activators of AMPK are known, including drugs in long use such as salicylate and metformin, and there is evidence that regular use of either of the latter provides protection against development of cancer. Tumor cells appear to be under selection pressure to down-regulate AMPK, thus limiting its restraining influence on cell growth and proliferation, and several interesting mechanisms by which this occurs are discussed. Paradoxically, however, a complete loss of AMPK function, which appears to be rare in human cancers, may be deleterious to survival of tumor cells. AMPK can therefore either be a friend and a foe in cancer, depending on the context

AMPK:a cellular energy sensor primarily regulated by AMP

AMPK (AMP-activated protein kinase) is a cellular energy sensor that monitors the ratio of AMP/ATP, and possibly also ADP/ATP, inside cells. Once activated by falling cellular energy levels, it acts to restore energy homoeostasis by switching on catabolic pathways that generate ATP, while switching off anabolic pathways and other processes consuming ATP. AMPK is switched on by increases in AMP via three mechanisms, all of which are antagonized by ATP: (i) promotion of phosphorylation of Thr172 by upstream activating kinases; (ii) inhibition of dephosphorylation of Thr172 by phosphatases; and (iii) allosteric activation of the phosphorylated kinase. Recently, it has been proposed that the first two mechanisms are also triggered by ADP, which might be the physiological signal rather than AMP, and that the third mechanism may not be physiologically significant. We have re-evaluated these questions, and found that only mechanism (ii) is mimicked by ADP, and that ADP is also less potent than AMP, which we still believe to be the primary signal. We have also provided evidence that mechanism (iii), i.e. allosteric activation by AMP, is a quantitatively significant mechanism in intact cells.</jats:p

Targeting an energy sensor to treat diabetes

Obesity occurs when whole-body energy intake exceeds energy expenditure for prolonged periods. This is a major public health issue because obesity increases the risk of disorders such as type 2 diabetes mellitus (T2DM). The liver and muscle store excess energy in the form of fat, leading to resistance to the hormone insulin. Released when blood glucose rises after meals, insulin normally promotes glucose uptake by muscle and represses glucose production by the liver, thus rapidly returning blood glucose to normal. However, this process is impaired in insulin-resistant individuals, who may eventually develop persistently elevated blood glucose (i.e., T2DM), which can cause debilitating or life-threatening complications. Because the energy sensor AMPK (adenosine monophosphate-activated protein kinase) promotes muscle glucose uptake by insulin-independent mechanisms, it was proposed in 1999 that AMPK-activating drugs might represent a novel approach to treating T2DM (1). Representing the culmination of more than 15 years of developing this concept, a study by Myers et al. (2) on page 507 of this issue and a study by Cokorinos et al. (3) show that compounds that bind to a unique site on AMPK can promote glucose uptake by muscle, and hence reverse elevated blood glucose in animal models of T2DM

AMPK:regulating energy balance at the cellular and whole body levels

AMP-activated protein kinase appears to have evolved in single-celled eukaryotes as an adenine nucleotide sensor that maintains energy homeostasis at the cellular level. However, during evolution of more complex multicellular organisms, the system has adapted to interact with hormones so that it also plays a key role in balancing energy intake and expenditure at the whole body level

Phenformin, but not metformin, delays development of T-cell acute lymphoblastic leukemia/lymphoma via cell-autonomous AMPK activation

Summary: AMPK acts downstream of the tumor suppressor LKB1, yet its role in cancer has been controversial. AMPK is activated by biguanides, such as metformin and phenformin, and metformin use in diabetics has been associated with reduced cancer risk. However, whether this is mediated by cell-autonomous AMPK activation within tumor progenitor cells has been unclear. We report that T-cell-specific loss of AMPK-α1 caused accelerated growth of T cell acute lymphoblastic leukemia/lymphoma (T-ALL) induced by PTEN loss in thymic T cell progenitors. Oral administration of phenformin, but not metformin, delayed onset and growth of lymphomas, but only when T cells expressed AMPK-α1. This differential effect of biguanides correlated with detection of phenformin, but not metformin, in thymus. Phenformin also enhanced apoptosis in T-ALL cells both in vivo and in vitro. Thus, AMPK-α1 can be a cell-autonomous tumor suppressor in the context of T-ALL, and phenformin may have potential for the prevention of some cancers. : The roles of AMPK in cancer and of biguanides in its prevention or treatment are controversial. Vara-Ciruelos et al. now report that genetic loss of AMPK in T cells accelerates T cell acute lymphoblastic leukemia/lymphoma, whereas the biguanide phenformin, but not metformin, protects against its development in a cell-autonomous, AMPK-dependent manner. Keywords: AMP-activated protein kinase, AMPK, biguanides, metformin, phenformin, T-ALL, T cell acute lymphoblastic leukemia/lymphom

Mechanism of Activation of AMPK by Cordycepin

Cordycepin (3′-deoxyadenosine) is a major bioactive agent in Cordyceps militaris, a fungus used in traditional Chinese medicine. It has been proposed to have many beneficial metabolic effects by activating AMP-activated protein kinase (AMPK), but the mechanism of activation remained uncertain. We report that cordycepin enters cells via adenosine transporters and is converted by cellular metabolism into mono-, di-, and triphosphates, which at high cordycepin concentrations can almost replace cellular adenine nucleotides. AMPK activation by cordycepin in intact cells correlates with the content of cordycepin monophosphate and not other cordycepin or adenine nucleotides. Genetic knockout of AMPK sensitizes cells to the cytotoxic effects of cordycepin. In cell-free assays, cordycepin monophosphate mimics all three effects of AMP on AMPK, while activation in cells is blocked by a γ-subunit mutation that prevents activation by AMP. Thus, cordycepin is a pro-drug that activates AMPK by being converted by cellular metabolism into the AMP analog cordycepin monophosphate.</p

AMPK as a direct sensor of long-chain fatty acyl–CoA esters

AMPK is a crucial sensor of the cellular energetic state and is also activated during glucose starvation. A new study reports that AMP-activated protein kinase (AMPK) is activated by interaction with long-chain fatty acyl–CoA esters, which appear to be the long-sought endogenous AMPK ligands that bind the allosteric drug and metabolite (ADaM) site

AMP-activated protein kinase - a journey from 1 to 100 downstream targets

A casual decision made one evening in 1976, in a bar near the Biochemistry Department at the University of Dundee, led me to start my personal research journey by following up a paper that suggested that acetyl-CoA carboxylase (ACC) (believed to be a key regulatory enzyme of fatty acid synthesis) was inactivated by phosphorylation by what appeared to be a novel, cyclic AMP-independent protein kinase. This led me to define and name the AMP-activated protein kinase (AMPK) signalling pathway, on which I am still working 46 years later. ACC was the first known downstream target for AMPK, but at least 100 others have now been identified. This article contains some personal reminiscences of that research journey, focussing on: (i) the early days when we were defining the kinase and developing the key tools required to study it; (ii) the late 1990s and early 2000s, an exciting time when we and others were identifying the upstream kinases; (iii) recent times when we have been studying the complex role of AMPK in cancer. The article is published in conjunction with the Sir Philip Randle Lecture of the Biochemical Society, which I gave in September 2022 at the European Workshop on AMPK and AMPK-related kinases in Clydebank, Scotland. During the early years of my research career, Sir Philip acted as a role model, due to his pioneering work on insulin signalling and the regulation of pyruvate dehydrogenase