Objectives/background: The P2X7 receptor for extracellular ATP recently emerged as regulator of cancer cell proliferation, energy production and migration (1). P2X7 expression has been demonstrated in a wide spectrum of tumour types including colon carcinoma, melanoma and neuroblastoma, all of which also showed P2X7-dependent growth in vivo (2). However, little is known about the intracellular events activated by P2X7 in cancer. Aim of our work was to identify the main biochemical ways responsible for P2X7 dependent cancer progression. Methods and results: The ability of P2X7 receptor to modulate intracellular calcium levels prompted us to investigate receptor-dependent PI3K/Akt pathway activation. In vitro and In vivo experiments in two models of neuroblastoma allowed us to demonstrate that P2X7 expression and activation positively influences the PI3K/Akt pathway. Moreover, P2X7 down-modulation, by either pharmacological blockade or silencing, reduced the activity of PI3K/Akt and increased that of GSK3β leading to a decrease in cellular glycogen stores. Up-modulation of GSK3βactivity by P2X7 antagonism also caused a significant reduction in the levels of probably the best-known oncogene in neuroblastoma: MYC-N (3). Increased number of blood vessels in P2X7 positive tumours, let us hypothesise that P2X7 might activate the main pathway involved in cancer vascularization that is the HIF1α-VEGF axis. Indeed, this proved to be the case as intratumoral VEGF levels resulted increased in a P2X7-dependent fashion in experimental models of colon carcinoma, melanoma and neuroblastoma (3,-5). Moreover, administration of the VEGF blocking antibody Avastin reduced P2X7-dependent cancer growth (4). In the neuroblastoma model, P2X7 also affected HIF1α levels both in vitro and ex vivo (3). Conclusion Taken together our data suggest that P2X7 receptor is an upstream regulator of the main signalling pathways involved in cancer growth, metabolic activity and angiogenesis, and a promising oncological therapeutic target.
ONCOGENIC PATHWAYS ACTIVATED BY P2X7
ADINOLFI, Elena
2015
Abstract
Objectives/background: The P2X7 receptor for extracellular ATP recently emerged as regulator of cancer cell proliferation, energy production and migration (1). P2X7 expression has been demonstrated in a wide spectrum of tumour types including colon carcinoma, melanoma and neuroblastoma, all of which also showed P2X7-dependent growth in vivo (2). However, little is known about the intracellular events activated by P2X7 in cancer. Aim of our work was to identify the main biochemical ways responsible for P2X7 dependent cancer progression. Methods and results: The ability of P2X7 receptor to modulate intracellular calcium levels prompted us to investigate receptor-dependent PI3K/Akt pathway activation. In vitro and In vivo experiments in two models of neuroblastoma allowed us to demonstrate that P2X7 expression and activation positively influences the PI3K/Akt pathway. Moreover, P2X7 down-modulation, by either pharmacological blockade or silencing, reduced the activity of PI3K/Akt and increased that of GSK3β leading to a decrease in cellular glycogen stores. Up-modulation of GSK3βactivity by P2X7 antagonism also caused a significant reduction in the levels of probably the best-known oncogene in neuroblastoma: MYC-N (3). Increased number of blood vessels in P2X7 positive tumours, let us hypothesise that P2X7 might activate the main pathway involved in cancer vascularization that is the HIF1α-VEGF axis. Indeed, this proved to be the case as intratumoral VEGF levels resulted increased in a P2X7-dependent fashion in experimental models of colon carcinoma, melanoma and neuroblastoma (3,-5). Moreover, administration of the VEGF blocking antibody Avastin reduced P2X7-dependent cancer growth (4). In the neuroblastoma model, P2X7 also affected HIF1α levels both in vitro and ex vivo (3). Conclusion Taken together our data suggest that P2X7 receptor is an upstream regulator of the main signalling pathways involved in cancer growth, metabolic activity and angiogenesis, and a promising oncological therapeutic target.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
