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.

• Authors: F Amoroso, S Falzoni, E Adinolfi, D Ferrari, F Di Virgilio
• Journal: Cell death & disease (Cell Death Dis) Vol. 3 Pg. e370 (Aug 16 2012) ISSN: 2041-4889 [Electronic] England
• PMID: 22898868 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glucose Transporter Type 1
• Hypoxia-Inducible Factor 1, alpha Subunit
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Receptors, Purinergic P2X7
• Lactic Acid
• Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone
• Adenosine Triphosphate
• Ketone Oxidoreductases
• Glyceraldehyde-3-Phosphate Dehydrogenases
• pyruvate dehydrogenase (NADP+)
• Phosphofructokinases
• Pyruvate Kinase
• 3-Phosphoinositide-Dependent Protein Kinases
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• 3-Phosphoinositide-Dependent Protein Kinases
• Adenosine Triphosphate (pharmacology)
• Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone (chemistry, pharmacology)
• Cell Line, Tumor
• Glucose Transporter Type 1 (genetics, metabolism)
• Glyceraldehyde-3-Phosphate Dehydrogenases (genetics, metabolism)
• Glycolysis (drug effects)
• HEK293 Cells
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Ketone Oxidoreductases (genetics, metabolism)
• Lactic Acid (metabolism)
• Phosphofructokinases (genetics, metabolism)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Pyruvate Kinase (genetics, metabolism)
• Receptors, Purinergic P2X7 (metabolism)
• Transfection
• Up-Regulation