In 1924 Otto Warburg hypothesized that the main cause of malignant transformation was the deviation of cancer cell metabolism towards direct conversion of pyruvate to lactate rather than its oxidation within the mitochondria. Persistence of glycolysis in the presence of normal oxygen concentrations (aerobic glycolysis) is now referred to as the “Warburg effect”. Although it is now clear that this peculiar glycolytic metabolism is not specific of cancer cells but of any fast growing cells, Warburg effect has met with rekindled interest in recent years after the discovery that some key oncogenes (e.g. AKT, c-myc), or suppressor genes (TP53, PTEN) affect expression and function of enzymes that control the glycolytic pathway, and that key glycolytic enzymes are overexpressed or dysregulated in cancer (e.g. pyruvate kinase isoform M2, hexokinase). Furthermore, these same oncogenes and oncosuppressor genes also profoundly modulate mitochondrial oxidative phosphorylation. Interrelationship between cancer genes, glycolysis and oxidative phosphorylation is intriguing because, contrary to previous opinion, it is now clear that mitochondrial respiration is by no means shut off in cancer cells. It appears that tumours set in motion all available machineries to secure the most efficient energy output (oxidative phosphorylation) and the highest production of building blocks for structural synthesis (glycolysis). In addition, several reports suggest that modulation of glycolysis or of selected enzymes involved in this pathway may arrest cancer cell growth and tumour progression. In recent years we have focused our attention on a plasma membrane receptor for extracellular ATP named P2X7. This receptor, which is a member of the P2 family, attracted our attention for the following reasons: a) is overxpressed by all human cancers so far investigated; b) has a strong trophic effect on mitochondria; c) stimulates oxidative phosphorylation; d) increases total cellular ATP content; e) causes activation of the transcription factor NFATc1. Furthermore, in vivo preliminary results show that: a) overexpression of P2X7 accelerates tumor growth and metastasis formation; b) silencing or pharmacological inhibition of P2X7 slows down tumor progression; c) P2X7 expression and activation drives VEGF secretion and angiogenesis; d) in primary human tumour cells and human tumour cell lines P2X7 is up-regulated and the NLRP3 inflammasome is down-modulated. Given the recent implication of mitochondria in the modulation of NLRP3 inflammasome activation under physiological conditions, our preliminary findings suggest that in cancer cells a dysregulation of the P2X7/mitochondria/inflammasome axis might be present. Collectively, these observations suggest that P2X7 might have an important and as yet neglected role in tumour growth. Therefore, we plan to carry out the following research program: a) investigate the effect of P2X7 expression/activation or silencing/inhibition on aerobic glycolysis in vitro (measured as lactate output); b) investigate the effect of P2X7 expression/activation or silencing/inhibition on expression and function selected glycolytic enzymes; c) investigate the effect of P2X expression/activation or silencing/inhibition on mitochondrial metabolism in established models of mouse tumours; d) investigate the effect of mitochondrial metabolism on NLRP3 inflammasome activity and cell growth; e) investigate the effect of NLRP3 inflammasome silencing on mitochondrial metabolism and on the Warburg effect.
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|Autori:||Di Virgilio, Francesco|
|Titolo:||AIRC IG 13025: The P2X7 receptor is a key switch of cancer cell glycolytic metabolism|
|Data di pubblicazione:||2014|
|Appare nelle tipologie:||08.1 Coordinamento Prog.Ricerca Naz. ed Internaz.|