Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
Department of Molecular and Tumour Pathology, Akita University Graduate School of Medicine, Akita, Japan.
Biochim Biophys Acta Mol Basis Dis. 2023 Oct;1869(7):166812. doi: 10.1016/j.bbadis.2023.166812. Epub 2023 Jul 16.
Gap junctions are specialized regions of the plasma membrane containing clusters of channels that provide for the diffusion of ions and small molecules between adjacent cells. A fundamental role of gap junctions is to coordinate the functions of cells in tissues. Cancer pathogenesis is usually associated with loss of intercellular communication mediated by gap junctions, which may affect tumor growth and the response to radio- and chemotherapy. Gap junction channels consist of integral membrane proteins termed connexins. In addition to their canonical roles in cell-cell communication, connexins modulate a range of signal transduction pathways via interactions with proteins such as β-catenin, c-Src, and PTEN. Consequently, connexins can regulate cellular processes such as cell growth, migration, and differentiation through both channel-dependent and independent mechanisms. Gap junctions are dynamic plasma membrane entities, and by modulating the rate at which connexins undergo endocytosis and sorting to lysosomes for degradation, cells can rapidly adjust the level of gap junctions in response to alterations in the intracellular or extracellular milieu. Current experimental evidence indicates that aberrant trafficking of connexins in the endocytic system is intrinsically involved in mediating the loss of gap junctions during carcinogenesis. This review highlights the role played by the endocytic system in controlling connexin degradation, and consequently gap junction levels, and discusses how dysregulation of these processes contributes to the loss of gap junctions during cancer development. We also discuss the therapeutic implications of aberrant endocytic trafficking of connexins in cancer cells.
间隙连接是质膜的特化区域，包含簇状通道，可促进相邻细胞之间的离子和小分子扩散。间隙连接的一个基本功能是协调组织中细胞的功能。癌症的发病机制通常与间隙连接介导的细胞间通讯丧失有关，这可能会影响肿瘤的生长和对放射和化学疗法的反应。间隙连接通道由称为连接蛋白的整合膜蛋白组成。除了在细胞间通讯中的典型作用外，连接蛋白还通过与β-连环蛋白、c-Src 和 PTEN 等蛋白相互作用来调节一系列信号转导途径。因此，连接蛋白可以通过通道依赖性和非依赖性机制调节细胞生长、迁移和分化等细胞过程。间隙连接是动态的质膜实体，通过调节连接蛋白内吞和分选到溶酶体进行降解的速度，细胞可以快速响应细胞内或细胞外环境的变化来调整间隙连接的水平。目前的实验证据表明，连接蛋白在内质网中的异常运输在介导致癌过程中间隙连接的丧失中起着内在作用。本文综述了内体系统在控制连接蛋白降解以及因此控制间隙连接水平方面的作用，并讨论了这些过程的失调如何导致癌症发展过程中间隙连接的丧失。我们还讨论了连接蛋白在癌细胞中的异常内吞运输的治疗意义。
