P2X7 Receptor: Warburg effect revisited

Ability to adapt to conditions of limited nutrient supply is a key feature of all cells. This may require a complex re-organization of metabolic pathways to balance energy generation and production of biosynthetic intermediates. Several fast-growing cells overexpress the P2X7 receptor (P2X7R) for extracellular ATP. A peculiar feature of this receptor is that it allows growth in the absence of serum. We show here that transfection of P2X7R allows proliferation of HEK293 (HEK293-P2X7) cells not only in the absence of serum but also in low (4 mM) glucose and strongly increases lactate output compared to mock-transfected cells (HEK293-mock). In HEK293-P2X7 lactate output is further stimulated upon addition of exogenous ATP or of the mitochondrial uncoupler FCCP. In another tumour cell line constitutively expressing the P2X7R, the human neuroblastoma cell line ACN, lactate output is also dependent on P2X7R function. P2X7R-expressing cells up-regulate a) the glucose transporter Glut-1, b) the glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase (G3PDH), c) pyruvate kinase M2 (PK-M2) and d) pyruvate dehydrogenase kinase 1 (PDHK1), e) increase phosphorylated Akt/PKB (ph- Akt/PKB) and f) the level of intracellular glycogen stores. In HEK293-P2X7 cells glucose deprivation strongly 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.