The P2X7 receptor is a key modulator of aerobic glycolysis

Abstract

Ability to adapt to conditions of limited nutrient supply requires a reorganization of the metabolic pathways to balance energy generation and production of biosynthetic intermediates. Several fast-growing cells overexpress the P2X7 receptor (P2X7R) for extracellular ATP. A feature of this receptor is to allow growth in the absence of serum. We show here that transfection of P2X7R allows proliferation of P2X7R-transfected HEK293 (HEK293-P2X7) cells not only in the absence of serum but also in low (4 mM) glucose, and increases lactate output compared with mock-transfected HEK293 (HEK293-mock) cells. In HEK293-P2X7, lactate output is further stimulated upon addition of exogenous ATP or the mitochondrial uncoupler carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP). In the human neuroblastoma cell line ACN, lactate output is also dependent on P2X7R function. P2X7R-expressing cells upregulate (a) the glucose transporter Glut1, (b) the glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase (G3PDH), (c) phosphofructokinase (PFK), (d) pyruvate kinase M2 (PKM2) and (e) pyruvate dehydrogenase kinase 1 (PDHK1); furthermore, P2X7R expression (a) inhibits pyruvate dehydrogenase (PDH) activity, (b) increases phosphorylated Akt/PKB and hypoxia-inducible factor 1α (HIF-1α) expression and (c) enhances intracellular glycogen stores. In HEK293-P2X7 cells, glucose deprivation increases lactate production, expression of glycolytic enzymes and ph-Akt/PKB level. These data show that the P2X7R has an intrinsic ability to reprogram cell metabolism to meet the needs imposed by adverse environmental conditions.

Loss of P2X7 nucleotide receptor function leads to abnormal fat distribution in mice

“…Grol and coworkers showed that activation of P2X7 leads to a dramatic, glucose-dependent increase in metabolic acid production by osteoblasts [31]. In addition, work from another lab has shown that heterologous expression of P2X7 in vitro leads to upregulation of glycolytic enzymes and an increase in lactate production [32]. Thus, overall energy expenditure may be less in mice lacking functional P2X7 receptors, resulting in increased accumulation of fat as the animals age.…”

“…This P2X7-induced increase in proton efflux is dependent on the activity of phosphatidylinositol 3-kinase and the presence of glucose. It has also been shown that heterologous expression of P2X7 in HEK293 cells promotes aerobic glycolysis and increases levels of glycolytic enzymes and glycogen stores [32]. Therefore, P2X7 activation enhances cellular energy metabolism, suggesting a role for this receptor in energy homeostasis.…”

The Therapeutic Potential of Modifying Inflammasomes and NOD-Like Receptors

“…A site of intersection between glycolysis and the inflammasomes might be the P2X7R. Very recently, we reported that cells expressing the P2X7R have a very active aerobic glycolysis and that agents known to stimulate aerobic glycolysis, such as mitochondrial uncouplers, require P2X7R expression (Amoroso et al, 2012). Interestingly, cells expressing the P2X7R overexpress key glycolytic enzymes such as glyceraldehyde 3-dehydrogenase, pyruvate kinase M2, pyruvate dehydrogenase kinase, and phosphofructokinase, as well as the transcription factor hypoxia inducible factor (HIF)-1a.…”

The P2X7 receptor is a key modulator of the PI3K/GSK3β/VEGF signaling network: evidence in experimental neuroblastoma

“…5 Extracellular ATP is the natural ligand of P2Y metabotropic and P2X inotropic receptors, among which P2X7 is the best candidate responsible for cancerassociated ATP effects, as it has shown an intriguing ability to confer a growth advantage to cancer cells in in vivo models. 1 The growth-promoting activity of P2X7 may be related to the proliferative advantage conferred to tumor cells under limiting growth conditions, such as serum and glucose deprivation, [6][7][8] to the stimulation of vascular endothelial growth factor (VEGF) secretion and to the facilitation of extracellular matrix invasion. 1,2,9 Although P2X7 expression and activity has been reported in several cancers 10,11 the tumor-promoting pathways activated by P2X7 are largely unknown.…”