AMPK: opposing the metabolic changes in both tumour cells and inflammatory cells?

Abstract

AMPK (AMP-activated protein kinase) is a sensor of cellular energy status that appears to have arisen during early eukaryotic evolution. In the unicellular eukaryote Saccharomyces cerevisiae, the AMPK orthologue is activated by glucose starvation and is required for the switch from glycolysis (fermentation) to oxidative metabolism when glucose runs low. In mammals, rapidly proliferating cells (including tumour cells) and immune cells involved in inflammation both tend to utilize rapid glucose uptake and glycolysis (termed the Warburg effect or aerobic glycolysis) rather than oxidative metabolism to satisfy their high demand for ATP. Since mammalian AMPK, similar to its yeast orthologue, tends to promote the more energy-efficient oxidative metabolism at the expense of glycolysis, it might be expected that drugs that activate AMPK would inhibit cell proliferation and and hence cancer, as well as exerting anti-inflammatory effects. Evidence supporting this view is discussed, including our findings that AMPK is activated by the classic anti-inflammatory drug salicylate.

Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling

“…It is becoming increasingly apparent that cells can couple inflammatory status to the availability of nutrients (51) (52). Conversely, the mechanisms by which nutrient availability can regulate inflammation remain unclear.…”

AMP-activated protein kinase signaling is upregulated in papillary thyroid cancer

“…Stresses that deplete energy and increase the intracellular AMP-to-ATP ratio induce allosteric activation of AMPK (1,2), promoting conformational changes that make the enzyme a better substrate for upstream kinases, which phosphorylate its Thr-172 residue and further activate AMPK. In its activated state, AMPK shuts down processes that consume energy and upregulates energy-producing pathways in an attempt to restore intracellular ATP levels (1,2,3). One of the well-described effects of AMPK is the inhibition of acetylCoA-carboxylase (ACC), an enzyme responsible for the conversion of acetyl-CoA to malonyl-CoA in de novo fatty acid biosynthesis.…”

“…AMP-activated protein kinase (AMPK) is a metabolic stress-sensing cytoplasmic enzyme composed of an a-catalytic and two regulatory subunits (b and g) (1). Stresses that deplete energy and increase the intracellular AMP-to-ATP ratio induce allosteric activation of AMPK (1,2), promoting conformational changes that make the enzyme a better substrate for upstream kinases, which phosphorylate its Thr-172 residue and further activate AMPK.…”

“…Malonyl-CoA is a potent inhibitor of carnitine palmitoyl transferase-1, responsible for the transport of long-chain fatty acid to mitochondrial matrix. The reduction of malonyl-CoA induced by AMPK activation thus favors fatty acid translocation into the mitochondria to be oxidized, in an attempt to restore intracellular ATP levels (1,2,3,4). Activation of AMPK can be evaluated by the use of a specific antibody that recognizes the catalytic subunits of AMPK when phosphorylated in Thr-172 residue (4).…”

Regulation of macrophage inflammatory signaling pathways by AMP-activated protein kinase.

“…The changes of the cytokine profile in the microenvironment induce macrophage subsequently shift their functional phenotypes, and display highly balanced patterns of inflammatory features (7,8). The AMP-activated protein kinase (AMPK) has been well established as a regulator of energy homeostasis in eukaryotic cells and recent research suggests an important role of AMPK as a counterregulator in many inflammatory processes (9)(10)(11)(12)(13). Our previous studies have shown that AMPK responds to either pro-or anti-inflammatory stimuli and plays a key regulatory role in macrophage and dendritic cell (DC) inflammatory functions (14,15).…”