Department of Molecular Pharmacology, Physiology, and Biotechnology, Center for Biomedical Engineering, Brown University, Providence, Rhode Island 02912, USA.
J Biol Chem. 2012 Mar 9;287(11):8407-16. doi: 10.1074/jbc.M111.306522. Epub 2012 Jan 20.
Pannexin 1 (Panx1) is a novel gap junction protein shown to have tumor-suppressive properties. To model its in vivo role in the intratumor biomechanical environment, we investigated whether Panx1 channels modulate the dynamic assembly of multicellular C6 glioma aggregates. Treatment with carbenoxolone and probenecid, which directly and specifically block Panx1 channels, respectively, showed that Panx1 is involved in accelerating aggregate assembly. Experiments further showed that exogenous ATP can reverse the inhibitive effects of carbenoxolone and that aggregate compaction is sensitive to the purinergic antagonist suramin. With a close examination of the F-actin microfilament network, these findings show that Panx1 channels act as conduits for ATP release that stimulate the P(2)X(7) purinergic receptor pathway, in turn up-regulating actomyosin function. Using a unique three-dimensional scaffold-free method to quantify multicellular interactions, this study shows that Panx1 is intimately involved in regulating intercellular biomechanical interactions pivotal in the progression of cancer.
连接蛋白 1（Panx1）是一种新型的间隙连接蛋白，具有肿瘤抑制特性。为了在肿瘤内生物力学环境中模拟其体内作用，我们研究了 Panx1 通道是否调节多细胞 C6 神经胶质瘤聚集体的动态组装。用 carbenoxolone 和 probenecid 处理，它们分别直接和特异性地阻断 Panx1 通道，表明 Panx1 参与加速聚集体的组装。实验进一步表明，外源性 ATP 可以逆转 carbenoxolone 的抑制作用，并且聚集的紧实度对嘌呤能拮抗剂苏拉明敏感。通过对 F-肌动蛋白微丝网络的仔细检查，这些发现表明 Panx1 通道充当 ATP 释放的通道，刺激 P(2)X(7)嘌呤能受体途径，进而上调肌动球蛋白的功能。使用独特的无支架三维方法来量化细胞间相互作用，这项研究表明 Panx1 密切参与调节细胞间生物力学相互作用，这对癌症的进展至关重要。
