Development of a Cx46 Targeting Strategy for Cancer Stem Cells
Development of a Cx46 Targeting Strategy for Cancer Stem Cells
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DOI：
10.1101/289397
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发表时间：
2018-03
期刊：
影响因子：
8.8
通讯作者：
E. Mulkearns-Hubert;Luke A. Torre-Healy;Daniel J. Silver;Jennifer T. Eurich;Defne Bayik;Emily Serbinowski;M. Hitomi;John Zhou;B. Przychodzen;Renliang Zhang;S. Sprowls;J. Hale;Tyler J. Alban;A. Berezovsky;B. Bell;P. Lockman;B. Jha;J. Lathia
中科院分区：
文献类型：
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作者：
E. Mulkearns-Hubert;Luke A. Torre-Healy;Daniel J. Silver;Jennifer T. Eurich;Defne Bayik;Emily Serbinowski;M. Hitomi;John Zhou;B. Przychodzen;Renliang Zhang;S. Sprowls;J. Hale;Tyler J. Alban;A. Berezovsky;B. Bell;P. Lockman;B. Jha;J. Lathia
间隙连接介导的细胞间通讯使肿瘤细胞能够同步执行复杂的过程。尽管间隙连接蛋白的连接蛋白家族被认为是肿瘤抑制因子，但我们以前发现，与非干肿瘤细胞相比，胶质母细胞瘤癌症干细胞（CSC）表达更高水平的Cx46，这对于CSC的维持是必要和足够的。为了开发Cx46靶向策略，我们利用点突变体来破坏Cx46的特定功能，并发现间隙连接偶联是Cx46对CSC的关键功能。基于这一发现，我们筛选了一个临床相关的小分子库，并确定氯法齐明作为Cx46特异性细胞间通讯的抑制剂。氯法齐明减弱增殖，自我更新，肿瘤生长和协同替莫唑胺诱导细胞凋亡。这些数据表明，将氯法齐明与标准治疗相结合可以靶向胶质母细胞瘤CSC。此外，这些结果证明了靶向细胞间通讯作为抗癌疗法的重要性。
Gap junction-mediated cell-cell communication enables tumor cells to synchronize the execution of complex processes. Despite the connexin family of gap junction proteins being considered tumor suppressors, we previously found that glioblastoma cancer stem cells (CSCs) express higher levels of Cx46 compared to non-stem tumor cells, and this was necessary and sufficient for CSC maintenance. To develop a Cx46 targeting strategy, we utilized point mutants to disrupt specific functions of Cx46 and found that gap junction coupling was the critical function of Cx46 for CSCs. Based on this finding, we screened a clinically relevant library of small molecules and identified clofazimine as an inhibitor of Cx46-specific cell-cell communication. Clofazimine attenuated proliferation, self-renewal, and tumor growth and synergized with temozolomide to induce apoptosis. These data suggest that combining clofazimine with standard-of-care therapies may target glioblastoma CSCs. Furthermore, these results demonstrate the importance of targeting cell-cell communication as an anti-cancer therapy.