The role of X-box binding protein-1 in tumorigenicity.
The role of X-box binding protein-1 in tumorigenicity.
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DOI：
10.1358/dnp.2009.22.5.1378631
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发表时间：
2009-06
影响因子：
--
通讯作者：
Clarke R
中科院分区：
文献类型：
--
作者：
Shajahan AN;Riggins RB;Clarke R
肿瘤的快速生长会使为其提供营养和氧气的血管系统不堪重负。在这种肿瘤内部，细胞经历内质网（EnR）应激，但可以通过一种称为未折叠蛋白反应（UPR）的适应性机制在这种不利的微环境中生存。X-box结合蛋白-1 （XBP-1）是UPR的关键转录激活因子，在细胞存活过程中负责调节基因功能。XBP-1(U) mRNA的非常规剪接导致两种蛋白质：XBP-1(S)在各种人类癌症中经常增加，而未剪接的XBP-1(U) mRNA的任何翻译蛋白作为内源性XBP-1(S)作用的显性阴性。在癌细胞中，过表达XBP-1可通过阻止药物诱导的细胞周期阻滞和线粒体通透性和凋亡而赋予耐药性，而下调XBP-1可增加对缺氧杀伤的敏感性。XBP-1还参与细胞去分化、癌病毒感染和上皮-间质转化（EMT）。鉴于XBP-1在肿瘤发生过程中介导了广泛的应答，关注XBP-1作为抗癌治疗靶点是合乎逻辑的。此外，XBP-1抑制剂与其他抗upr药物联合使用可能会增强某些抗肿瘤治疗的活性。
Rapid growth of a tumor can overwhelm the vasculature that supplies it with nutrients and oxygen. Inside such tumors, cells undergo endoplasmic reticulum (EnR) stress but can survive such adverse microenvironments by an adaptive mechanism called the unfolded protein response (UPR). X-box binding protein-1 (XBP-1) is a critical transcriptional activator of the UPR and is responsible for regulating the function of genes in cell survival. An unconventional splicing of the XBP-1(U) mRNA results in two proteins: XBP-1(S) that is often increased in a variety of human cancers, and any translated proteins from the unspliced XBP-1(U) mRNA that acts as a dominant negative of endogenous XBP-1(S) action. In cancer cells, over-expression of XBP-1 can confer drug resistance by preventing drug-induced cell cycle arrest and mitochondrial permeability and apoptosis while down-regulation of XBP-1 increases the sensitivity to killing by hypoxia. XBP-1 is also implicated in cellular de-differentiation, oncovirus infection and the epithelial-to-mesenchymal transition (EMT). Given that XBP-1 mediates a wide range of responses in tumorigenesis, it is logical to focus on XBP-1 as an anti-cancer therapeutic target. Furthermore, combining inhibitors of XBP-1 with other anti-UPR drugs may enhance the activity of some anti-neoplastic therapies.
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