P2X7: a growth-promoting receptor—implications for cancer

Abstract

The P2X 7 receptor is widely referred to as the paradigmatic cytotoxic nucleotide receptor, and is often taken as an epitome of cytotoxic receptors as a whole. However, cytotoxicity is the result of sustained pharmacological stimulation, which is likely to occur in vivo only under severe pathological conditions. Over the years, we have gathered robust experimental proof that led us to adopt an entirely different view, pointing to P2X 7 as a survival/growth-promoting rather than death-inducing receptor. Evidence in favour of this role is manifold: (1) extracellular ATP and benzoyl ATP support cell proliferation in peripheral T lymphocytes via a P2X 7 -like receptor; (2) P2X 7 transfection into several cell lines confers growth advantage; (3) HEK293 cells transfected with P2X 7 show enhanced mitochondrial metabolic activity and growth; (4) lipopolysaccharide (LPS)-dependent growth arrest of microglia is mediated via P2X 7 down-modulation; (5) several malignant tumours express high P2X 7 levels and (6) the ATP concentration in tumour interstitium is severalfold higher than in healthy tissues, to a level in principle sufficient to activate the P2X 7 receptor. The molecular basis of P2X 7 -mediated growth-promoting activity is poorly known, but mitochondria appear to play a central role. A deeper understanding of the role played by P2X 7 in cell proliferation might provide an insight into the mechanism of normal and malignant cell growth and suggest novel anti-tumour therapies.

P2X7 receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness

“…In fact, among all cancer types tested, cervical cancer is the only exception to our knowledge with a decreased expression of P2X 7 R in cancer cells (Li et al, 2006). Contrarily to initial assumptions, P2X 7 R were reported to have anti-apoptotic effects (Deli et al, 2007) and even to promote cell growth (Adinolfi et al, 2005;Raffaghello et al, 2006;Di Virgilio et al, 2009) in some cancer cells. All these studies mainly focused on the regulation of cell proliferation/apoptosis and other important parameters such as cancer cell invasiveness were not assessed.…”

“…One possible explanation for this could be the tonic release of ATP by cancer cells responsible for autocrine/paracrine regulations. Indeed, P2X 7 R have already been demonstrated to be responsible for trophic activities on different cell types, including cancer cells, in the absence of ATP stimulation (Adinolfi et al, 2005(Adinolfi et al, , 2010Di Virgilio et al, 2009). Alternatively, one other hypothesis could be a basal, channel-independent, activity of the receptor in the complete absence of any purinergic stimulation.…”

Natural compounds with P2X7 receptor-modulating properties

“…In some cases, P2X7 activation by ATP causes a decrease in tumour cell number [30][31][32][33]. On the contrary, P2X7 activation may support cell proliferation, tumour growth or metastatic activity [34,35]. Thus, for instance in human breast cancer cells or in a rat brain glioblastoma model, inhibition of P2X7 has been suggested as potential therapeutic strategy to slow the progression of tumours [36,37].…”

Conserved ectodomain cysteines are essential for rat P2X7 receptor trafficking

“…For P2X7R, trafficking to the plasma membrane is also of significant physiological relevance. For example, P2X7Rs are abnormally expressed in some types of cancer [16,31,42] and participate in the control of cell proliferation [1,11]. In monocytes and lymphocytes, the receptors are predominantly intracellular [20], whereas when monocytes differentiate into macrophages, there is a large increase in their surface expression and function [21].…”