Differential connexin function enhances self-renewal in glioblastoma.
Differential connexin function enhances self-renewal in glioblastoma.
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DOI：
10.1016/j.celrep.2015.04.021
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发表时间：
2015-05-19
期刊：
影响因子：
8.8
通讯作者：
Lathia JD
中科院分区：
文献类型：
--
作者：
Hitomi M;Deleyrolle LP;Mulkearns-Hubert EE;Jarrar A;Li M;Sinyuk M;Otvos B;Brunet S;Flavahan WA;Hubert CG;Goan W;Hale JS;Alvarado AG;Zhang A;Rohaus M;Oli M;Vedam-Mai V;Fortin JM;Futch HS;Griffith B;Wu Q;Xia CH;Gong X;Ahluwalia MS;Rich JN;Reynolds BA;Lathia JD
复杂肿瘤过程的协调需要细胞快速改变其表型，这是通过连接蛋白组成的间隙连接通道直接细胞间通讯来实现的。先前的报告表明间隙连接基于连接蛋白43 (Cx43) 具有肿瘤抑制作用，但这并没有考虑到驱动间隙连接多样性的连接蛋白介导的离子选择性和细胞间通讯速率的差异。我们发现胶质母细胞瘤干细胞（CSC）具有功能性间隙连接，可以使用临床相关化合物来靶向这些间隙连接，以减少自我更新和肿瘤生长。我们的分析表明，CSC 表达 Cx46，而 Cx43 主要在非 CSC 中表达。在分化过程中，Cx46 减少，而 Cx43 增加，针对 Cx46 会损害 CSC 的维持。 Cx46 和 Cx43 之间的差异反映在 CSC 中细胞间通讯的增强和静息膜电位的降低。我们的数据证明间隙连接的促肿瘤作用依赖于连接蛋白的表达。
The coordination of complex tumor processes requires cells to rapidly modify their phenotype and is achieved by direct cell-cell communication through gap junction channels composed of connexins. Previous reports have suggested that gap junctions are tumor suppressive based on connexin43 (Cx43), but this does not take into account differences in connexin-mediated ion selectivity and intercellular communication rate that drive gap junction diversity. We find that glioblastoma cancer stem cells (CSCs) possess functional gap junctions that can be targeted using clinically relevant compounds to reduce self-renewal and tumor growth. Our analysis reveals that CSCs express Cx46, while Cx43 is predominantly expressed in non-CSCs. During differentiation, Cx46 is reduced, while Cx43 is increased, and targeting Cx46 compromises CSC maintenance. The difference between Cx46 and Cx43 is reflected in elevated cell-cell communication and reduced resting membrane potential in CSCs. Our data demonstrate a pro-tumorigenic role for gap junctions that is dependent on connexin expression.