Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.
Cell Rep. 2019 Apr 23;27(4):1062-1072.e5. doi: 10.1016/j.celrep.2019.03.079.
Gap-junction-mediated cell-cell communication enables tumor cells to synchronize complex processes. We previously found that glioblastoma cancer stem cells (CSCs) express higher levels of the gap junction protein Cx46 compared to non-stem tumor cells (non-CSCs) and that this was necessary and sufficient for CSC maintenance. To understand the mechanism underlying this requirement, we use point mutants to disrupt specific functions of Cx46 and find that Cx46-mediated gap-junction coupling is critical for CSCs. To develop a Cx46 targeting strategy, we screen a clinically relevant small molecule library and identify clofazimine as an inhibitor of Cx46-specific cell-cell communication. Clofazimine attenuates proliferation, self-renewal, and tumor growth and synergizes with temozolomide to induce apoptosis. Although clofazimine does not cross the blood-brain barrier, the combination of clofazimine derivatives optimized for brain penetrance 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.
缝隙连接介导的细胞间通讯使肿瘤细胞能够同步复杂的过程。我们之前发现，与非干细胞肿瘤细胞 (non-CSCs) 相比，神经胶质瘤癌症干细胞 (CSCs) 表达更高水平的缝隙连接蛋白 Cx46，并且这对于 CSC 的维持是必要和充分的。为了了解这一要求的机制，我们使用点突变来破坏 Cx46 的特定功能，并发现 Cx46 介导的缝隙连接偶联对于 CSCs 至关重要。为了开发针对 Cx46 的策略，我们筛选了一个临床相关的小分子文库，并确定氯苯吩嗪是 Cx46 特异性细胞间通讯的抑制剂。氯苯吩嗪可抑制增殖、自我更新和肿瘤生长，并与替莫唑胺协同诱导细胞凋亡。虽然氯苯吩嗪不能穿过血脑屏障，但针对脑穿透性优化的氯苯吩嗪衍生物与标准治疗方法的联合应用可能靶向神经胶质瘤 CSCs。此外，这些结果表明靶向细胞间通讯作为一种抗癌疗法的重要性。
