ATP in the tumour microenvironment drives expression of nfP2X(7), a key mediator of cancer cell survival.
ATP in the tumour microenvironment drives expression of nfP2X(7), a key mediator of cancer cell survival.
复制标题
DOI：
10.1038/s41388-018-0426-6
复制
发表时间：
2019-01
期刊：
影响因子：
8
通讯作者：
Lara R
中科院分区：
文献类型：
--
作者：
Gilbert SM;Oliphant CJ;Hassan S;Peille AL;Bronsert P;Falzoni S;Di Virgilio F;McNulty S;Lara R
ATP门控受体P2X7在多种恶性肿瘤中表达，包括神经母细胞瘤、黑色素瘤、前列腺、肺癌和乳腺癌。 P2X7 在介导多种细胞反应中发挥着重要作用，其失调与肿瘤的发生和发展相关。 ATP 介导的 P2X7 快速激活会在细胞中诱导快速内向阳离子电流。然而，长时间 ATP 介导的 P2X7 激活会导致孔的形成，从而增加膜通透性并最终导致细胞死亡。这提出了一个潜在的悖论，因为肿瘤微环境中含有足以激活 P2X7 孔并引发细胞死亡的细胞外 ATP。然而，P2X7 表达与癌细胞存活、增殖和转移潜力增强相关。已经描述了至少一种独特的 P2X7 构象形式，称为非孔功能性 P2X7 (nfP2X7)，它不能形成功能性孔。我们在这项研究中首次证明，暴露于高 ATP 浓度（相当于在肿瘤微环境中测量的浓度）会驱动 nfP2X7 表达，而且 nfP2X7 对于肿瘤细胞的存活至关重要。我们发现针对 P2X7 氨基酸序列 (200-216) 的单克隆抗体（其构象与野生型 (WT) P2X7 不同）特异性结合肿瘤细胞表面表达的 nfP2X7。我们还表明，nfP2X7 在多种癌症的患者来源肿瘤切片中广泛表达。因此，针对 E200 产生的抗体提供了可以区分在癌症中起关键作用的 P2X7 受体形式的工具。
The ATP-gated receptor P2X7 is expressed in multiple malignant tumours including neuroblastoma, melanoma, prostate, lung and breast. P2X7 has a significant role in mediating diverse cell responses, which upon dysregulation are associated with tumour initiation and development. The rapid, ATP-mediated activation of P2X7 induces a fast-inward cation current in cells. However, prolonged ATP-mediated activation of P2X7 leads to formation of a pore that increases membrane permeability and eventually causes cell death. This presents a potential paradox, as the tumour microenvironment contains extracellular ATP at levels sufficient to activate the P2X7 pore and trigger cell death. However, P2X7 expression is associated with enhanced cancer cell survival, proliferation and metastatic potential. At least one distinct conformational form of P2X7, termed non-pore functional P2X7 (nfP2X7), has been described, which is not able to form a functional pore. We demonstrate for the first time in this study that exposure to a high ATP concentration, equivalent to those measured in the tumour microenvironment, drives nfP2X7 expression and also that nfP2X7 is essential for tumour cell survival. We show that monoclonal antibodies raised against a P2X7 amino acid sequence (200–216), whose conformation is distinct from that of wild-type (WT) P2X7, bind specifically to nfP2X7 expressed on the surface of tumour cells. We also show that nfP2X7 is broadly expressed in patient-derived tumour sections from a wide range of cancers. Therefore, antibodies raised against E200 provide tools that can differentiate between forms of the P2X7 receptor that have a key role in cancer.
登录
查看更多内容
影响因子：
--
作者：
Amoroso F;Salaro E;Falzoni S;Chiozzi P;Giuliani AL;Cavallesco G;Maniscalco P;Puozzo A;Bononi I;Martini F;Tognon M;Di Virgilio F
通讯作者：
Di Virgilio F
DOI：
10.1073/pnas.85.21.7988
发表时间：
1988-11-01
影响因子：
11.1
作者：
BUISMAN, HP;STEINBERG, TH;LEIJH, PCJ
通讯作者：
LEIJH, PCJ
影响因子：
4.8
作者：
Feng, Ying-Hong;Li, Xin;Gorodeski, George I.
通讯作者：
Gorodeski, George I.
影响因子：
10.3
作者：
Gilbert, S. M.;Baird, A. Gidley;King, J.
通讯作者：
King, J.
DOI：
10.1152/ajpcell.2000.279.4.c1189
发表时间：
2000-10-01
影响因子：
5.5
作者：
Gu, BJ;Zhang, WY;Wiley, JS
通讯作者：
Wiley, JS