肿瘤微环境中Na (+)/H(+)交换:NHE1是否驱动乳腺癌的发生?

S. R. Amith, Sunny Fong, S. Baksh, L. Fliegel
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引用次数: 35

摘要

离子信使在癌变过程中发出几个关键事件的信号,包括转移,这是导致患者死亡的主要原因。肿瘤细胞的异常代谢、增殖和抗凋亡性质可追溯到其离子转运体和相关信号网络的异常表达。在这篇文章中,我们讨论了钠-氢交换异构体1 (NHE1)介导的Na(+)/H(+)通量,NHE1是参与肿瘤发生的主要离子转运体。外部刺激对NHE1的变构激活是由胞质c端尾部关键氨基酸的磷酸化控制的,它也作为细胞内蛋白和脂质结合伙伴调控的信号支架。在乳腺癌细胞中,pH稳态和质子动力学在转化早期被破坏。这构成性地激活NHE1,引起质膜pH梯度的逆转,导致细胞内pH值更碱性,细胞外pH值更酸性。NHE1介导的细胞碱化增强了细胞骨架重塑,动员细胞进行定向迁移。与此同时,NHE1重新分布到侵过体,在那里增加的质子挤压促进了细胞外基质的蛋白水解消化,为细胞侵入血流做好了准备。因此,NHE1的过度活跃预示着癌细胞发展的一个重要阶段,关键地促进了转移发生所需的侵袭性表型的获得。探讨了靶向NHE1在开发新型化疗应用中的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Na (+)/H (+)exchange in the tumour microenvironment: does NHE1 drive breast cancer carcinogenesis?
Ionic messengers signal several critical events in carcinogenesis, including metastasis, the leading cause of patient mortality. The aberrant metabolic, proliferative and anti-apoptotic nature of neoplastic cells can be traced to the abnormal expression of their ion transporters and related signalling networks. In this manuscript, we discuss Na(+)/H(+)flux, as mediated by the sodium-hydrogen exchanger isoform 1 (NHE1), a major ion transporter involved in tumourigenesis. Allosteric activation of NHE1 by external stimuli is controlled by phosphorylation of key amino acids on its cytosolic C-terminal tail, which also acts as a signal scaffold for its regulation by intracellular protein and lipid binding partners. In breast cancer cells, pH homeostasis and proton dynamics are disrupted early in transformation. This constitutively activates NHE1, causing a reversal of the plasma membrane pH gradient, resulting in a more alkaline intracellular pH and a more acidic extracellular pH. NHE1-mediated cellular alkalinization potentiates cytoskeletal remodelling, mobilizing cells for directed migration. Concomitant redistribution of NHE1 to invadopodia, where increased proton extrusion promotes proteolytic digestion of the extracellular matrix, primes cells for invasion into the bloodstream. NHE1 hyperactivity therefore heralds an important stage in cancer cell development, critically facilitating the acquisition of the invasive phenotype necessary for metastasis to occur. The potential for targeting NHE1 in the development of novel chemotherapeutic applications is explored.
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