文章：

葡萄糖调节蛋白在癌症中的作用：分子机制和治疗潜力

Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential

原文发布日期：2014-03-24

DOI: 10.1038/nrc3701

类型: Review Article

开放获取: 否

要点：

1. The glucose-regulated proteins (GRPs) GRP78, GRP94, GRP170 and GRP75, are members of the heat shock protein family. They primarily reside in the endoplasmic reticulum (ER) or the mitochondria, and they are induced at the transcriptional level upon ER stress.
2. As molecular chaperones, the GRPs regulate protein quality control and degradation, with GRP78 additionally functioning as a pivotal regulator of the unfolded protein response and the apoptotic machinery that is associated with the ER.
3. The GRPs can be actively translocated to other cellular locations and secreted, and they can assume additional functions that control cellular signalling, proliferation, invasion, apoptosis, inflammation and immunity, which have major implications in cancer progression and therapeutic resistance.
4. Specific roles of GRPs in development, tumorigenesis, metastasis and angiogenesis have been identified in vitro and are supported by genetically engineered mouse models.
5. GRP overexpression is widely reported in many human cancers and is associated with aggressive properties, which suggests that GRPs have potential prognostic value. Interfering with the production or activities of GRPs in tumours that overexpress these proteins might provide new approaches for cancer treatment.
6. The discovery that cell surface GRP78 is preferably expressed in cancer cells and stressed endothelial cells has led to the development of therapeutic agents that specifically target cell surface GRP78. These agents can induce cancer cell apoptosis and suppress tumorigenesis in mouse models with minimal toxicity.
7. Although the GRPs are attractive targets for drug development, they can also function as mediators for cancer-specific drug delivery, transcriptional targeting of cancer and vaccine development.
8. GRP170 can present full-length antigens to induce an immune response, which suggests that GRP170 could function as part of a new vaccine platform to augment antitumour immune responses.

要点翻译：

1. 葡萄糖调节蛋白（GRPs）GRP78、GRP94、GRP170和GRP75是热休克蛋白家族的成员。它们主要存在于内质网或线粒体中，并在内质网应激时在转录水平被诱导。
2. 作为分子伴侣，GRPs调控蛋白质质量控制和降解，其中GRP78还作为未折叠蛋白反应及内质网相关凋亡机制的关键调控因子。
3. GRPs能够主动转运至其他细胞位置并被分泌，可承担调控细胞信号传导、增殖、侵袭、凋亡、炎症及免疫的附加功能，这些功能对癌症进展和治疗抵抗具有重要影响。
4. GRPs在发育、肿瘤发生、转移和血管生成中的具体作用已在体外实验中得到确认，并获基因工程小鼠模型支持。
5. GRP过表达在多种人类癌症中被广泛报道，且与侵袭性特征相关，表明GRPs具有潜在预后价值。在过表达GRPs的肿瘤中干预其产生或活性，可能为癌症治疗提供新途径。
6. 细胞表面GRP78优先在癌细胞和应激内皮细胞中表达的发现，推动了特异性靶向细胞表面GRP78的治疗剂研发。这些药物能在小鼠模型中诱导癌细胞凋亡并抑制肿瘤发生，且毒性极小。
7. 尽管GRPs是药物开发的有吸引力的靶点，它们也可作为癌症特异性药物递送、癌症转录靶向及疫苗开发的媒介。
8. GRP170能呈递全长抗原诱导免疫应答，表明其可作为新型疫苗平台的组成部分以增强抗肿瘤免疫反应。

英文摘要：

The glucose-regulated proteins (GRPs) are stress-inducible chaperones that mostly reside in the endoplasmic reticulum or the mitochondria. Recent advances show that the GRPs have functions that are distinct from those of the related heat shock proteins, and they can be actively translocated to other cellular locations and assume novel functions that control signalling, proliferation, invasion, apoptosis, inflammation and immunity. Mouse models further identified their specific roles in development, tumorigenesis, metastasis and angiogenesis. This Review describes their discovery and regulation, as well as their biological functions in cancer. Promising agents that use or target the GRPs are being developed, and their efficacy as anticancer therapeutics is also discussed.

摘要翻译： 

葡萄糖调节蛋白（GRPs）是一类可被应激诱导的分子伴侣，主要定位于内质网或线粒体。最新研究表明，GRPs的功能与相关热休克蛋白不同，它们可被主动转运至其他细胞部位，获得调控信号传导、增殖、侵袭、凋亡、炎症及免疫的新功能。小鼠模型进一步揭示了其在发育、肿瘤发生、转移和血管生成中的特异作用。本综述阐述其发现与调控机制，以及在癌症中的生物学功能。利用或靶向GRPs的有前景药物正在研发中，其作为抗癌治疗的疗效亦被讨论。

原文链接：

Glucose-regulated proteins in cancer: molecular mechanisms and therapeutic potential