The P2X7 receptor is a key modulator of aerobic glycolysis.

Adaptation to limited nutrient supply is a key survival factor for normal and transformed cells.1 This phenomenon involves complex biochemical and metabolic changes that affect ATP synthesis and production of intermediates needed for the synthesis of basic cell constituents (lipids and nucleic acid). A key aspect of cell adaptation to unfavorable ambient conditions is the modulation of energy metabolism. The most important substrate used for generation of ATP or building blocks for nucleic-acid, amino-acid or lipid synthesis is glucose. Glucose deprivation triggers a complex adaptation response referred to as unfolded protein response (UPR) that involves mainly, but not exclusively, the endoplasmic reticulum (ER). UPR allows a profound reshaping of cancer cell metabolism that increases survival, progression and resistance to chemotherapics.2 The molecular basis of the better adaptation of tumors to low glucose is not clear, albeit several mechanisms have been invoked, such as a reprogramming of mitochondria, repression of the CC3/TIP30 gene or downregulation of specific micro RNA (e.g. miR-451).3, 4, 5 Tumor adaptation to low glucose intersects with another burning aspect of cancer cell biology, the rediscovered Warburg effect, that is, the persistence of high glycolytic rates in the presence of near-physiological oxygen levels.6 In fact, it has been known for over 70 years that tumors have a high glycolytic metabolism that preferentially generates lactate rather than funnelling pyruvate to Krebs cycle.7 More recently, it has become clear that the Warburg effect is not an exclusive feature of cancer cells, as rapidly proliferating cells also may exhibit a strong glycolytic metabolism in the presence of oxygen.8 Aerobic glycolysis involves, and might be modulated by, changes in the expression of several enzymes of the glycolytic pathway, for example, hexokinase, phosphofructokinase (PFK), glyceraldehyde 3-phosphate dehydrogenase (G3PDH), pyruvate kinase M2 (PKM2), as well as enzymes specifically controlling pyruvate entry into the Krebs cycle, such as pyruvate dehydrogenase kinase1 (PDHK1).9 If and how these enzymes are also modulated under conditions of limited glucose availability is not known. In the past, we have investigated the metabolic effects of the P2X7 receptor (P2X7R), a member of the P2 receptor family. P2X7R is an ATP-gated plasma-membrane ion channel that traditionally has been associated to cytotoxicity,10 however, growing evidence now suggest that its tonic, as opposed to sustained, activity exerts a strong trophic effect.11, 12, 13 We and others have shown that P2X7R expression is necessary for proliferation of T and B lymphocytes and microglial cells.14, 15, 16, 17 Furthermore, P2X7R is also involved in T-cell differentiation and Ag-specific dendritic cell activation.18, 19, 20 We have extensively investigated the growth-promoting activity of P2X7R, both in cells expressing the native receptor and in heterologous expression cellular models, for example, HEK293 or Hela cells.12 HEK293 cells are a good model to investigate P2X7R function as they on one hand have no endogenous P2X7R and on the other can be easily transfected. Upon P2X7R transfection, HEK293 cells acquire the ability to grow in the absence of serum. This growth advantage depends on a strong increase in the efficiency of mitochondrial oxidative phosphorylation, an increased cellular ATP content, an improved ER Ca2+ handling and an increased activation of the transcription factor ‘nuclear factor of activated T-cell cytoplasmic 1' (NFATc1).12, 21 P2X7R-transfected cells have also an increased motility and a better ability to infiltrate soft agar and undergo metastatic dissemination in vivo.21, 22 In the present study, we report that P2X7R expression allows proliferation of HEK293 cells during the combined serum and glucose deprivation. P2X7R-transfected HEK293 (HEK293-P2X7) cells have a higher lactate output, overexpress several of the key glycolytic enzymes and the ubiquitous glucose transporter Glut1, have larger glycogen depots and show an increased level of phosphorylated Akt/PKB (ph-Akt/PKB) and hypoxia-inducible factor 1α (HIF-1α). In low glucose, expression of glycolytic enzymes is strongly upregulated in HEK293-P2X7, much less in wild-type or mock-transfected HEK293 (HEK293-mock) cells. These results show that P2X7R expression allows better adaptability to unfavorable ambient conditions via upregulation of glycolytic enzymes and by increasing intracellular glycogen stores, and may help to better understand cancer cell energy metabolism and tumor progression and dissemination.