Department of Experimental and Diagnostic Medicine, Section of General Pathology, and Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, Via Borsari 46, Ferrara, 44100, Italy,
Purinergic Signal. 2009 Jun;5(2):251-6. doi: 10.1007/s11302-009-9145-3. Epub 2009 Mar 4.
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 several-fold 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.
P2X(7) 受体通常被称为典范性细胞毒性核苷酸受体，并且常常被视为整个细胞毒性受体的代表。然而，细胞毒性是持续药理刺激的结果，这种刺激很可能仅在严重的病理条件下才会在体内发生。多年来，我们已经收集了强有力的实验证据，使我们采取了完全不同的观点，即 P2X(7) 是一种促进生存/生长而非诱导死亡的受体。支持这一作用的证据有很多：（1）细胞外 ATP 和苯甲酰基 ATP 通过类似于 P2X(7) 的受体支持外周 T 淋巴细胞的增殖；（2）将 P2X(7) 转染到几种细胞系中赋予生长优势；（3）转染 P2X(7) 的 HEK293 细胞显示出增强的线粒体代谢活性和生长；（4）脂多糖 (LPS) 依赖性小胶质细胞生长停滞是通过 P2X(7) 下调介导的；（5）几种恶性肿瘤表达高水平的 P2X(7)；（6）肿瘤间质中的 ATP 浓度比健康组织高几倍，原则上足以激活 P2X(7) 受体。P2X(7) 介导的促生长活性的分子基础知之甚少，但线粒体似乎起着核心作用。更深入地了解 P2X(7) 在细胞增殖中的作用可能有助于深入了解正常和恶性细胞生长的机制，并为新的抗肿瘤治疗提供思路。
