Shajahan Ayesha N, Riggins Rebecca B, Clarke Robert
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, D.C., USA.
Drug News Perspect. 2009 Jun;22(5):241-6. doi: 10.1358/dnp.2009.22.5.1378631.
Rapid growth of a tumor can overwhelm the vasculature that supplies it with nutrients and oxygen. Inside such tumors, cells undergo endoplasmic reticulum 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) messenger RNA (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, overexpression of XBP-1 can confer drug resistance by preventing drug-induced cell-cycle arrest and mitochondrial permeability and apoptosis, while downregulation 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. Given that XBP-1 mediates a wide range of responses in tumorigenesis, it is logical to focus on XBP-1 as an anticancer therapeutic target. Furthermore, combining inhibitors of XBP-1 with other anti-UPR drugs may enhance the activity of some antineoplastic therapies.
肿瘤的快速生长会使为其提供营养和氧气的脉管系统不堪重负。在这类肿瘤内部，细胞会经历内质网应激，但可通过一种名为未折叠蛋白反应（UPR）的适应性机制在这种不利的微环境中存活。X盒结合蛋白1（XBP-1）是UPR的关键转录激活因子，负责调节细胞存活相关基因的功能。XBP-1（U）信使核糖核酸（mRNA）的非常规剪接产生两种蛋白质：XBP-1（S），其在多种人类癌症中通常会增加；以及来自未剪接的XBP-1（U）mRNA的任何翻译蛋白，其作为内源性XBP-1（S）作用的显性负性因子。在癌细胞中，XBP-1的过表达可通过防止药物诱导的细胞周期停滞、线粒体通透性和凋亡来赋予耐药性，而XBP-1的下调会增加对缺氧杀伤的敏感性。XBP-1还与细胞去分化、肿瘤病毒感染以及上皮-间质转化有关。鉴于XBP-1在肿瘤发生过程中介导广泛的反应，将XBP-1作为抗癌治疗靶点是合乎逻辑的。此外，将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。
