Pannexin1 Drives Multicellular Aggregate Compaction via a Signaling Cascade That Remodels the Actin Cytoskeleton
Pannexin1 Drives Multicellular Aggregate Compaction via a Signaling Cascade That Remodels the Actin Cytoskeleton
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DOI：
10.1074/jbc.m111.306522
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发表时间：
2012-03-09
影响因子：
4.8
通讯作者：
Morgan, Jeffrey R.
中科院分区：
文献类型：
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作者：
Bao, Brian A.;Lai, Charles P.;Morgan, Jeffrey R.
Pannexin 1（Panx 1）是一种新型的间隙连接蛋白，具有肿瘤抑制特性。为了模拟其在肿瘤内生物力学环境中的体内作用，我们研究了Panx 1通道是否调节多细胞C6胶质瘤聚集体的动态组装。甘珀酸和丙磺舒，直接和特异性阻断Panx 1通道，分别处理表明，Panx 1参与加速聚集体组装。实验进一步表明，外源性ATP可以逆转甘珀酸的抑制作用，聚集体致密化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Panx 1通道作为ATP释放的管道，刺激P2 X7嘌呤能受体途径，进而上调肌动球蛋白功能。使用独特的三维无支架方法来量化多细胞相互作用，这项研究表明Panx 1密切参与调节细胞间生物力学相互作用，这在癌症进展中至关重要。
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 P2X7 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.