文章：

未折叠蛋白反应在肿瘤发展中的作用：是敌是友？

The role of the unfolded protein response in tumour development: friend or foe?

原文发布日期：2004-12-01

DOI: 10.1038/nrc1505

类型: Review Article

开放获取: 否

要点：

1. When eukaryotic cells encounter adverse physiological conditions that impact on protein folding in the endoplasmic reticulum, a signal-transduction cascade is activated; this is termed the unfolded protein response (UPR).
2. The UPR is a multipronged response that is largely cytoprotective, but under conditions of prolonged stress apoptotic components are activated.
3. The UPR can be activated in tumours; this is apparently due to their inadequate vascularization. This results in limited oxygen and nutrients, which impinge on the normal maturation of secretory-pathway proteins.
4. Activation of the UPR might promote dormancy, aid tumour growth or protect the host by inducing apoptosis. It is presently unclear where the balance lies and how the fate of a tumour cell is eventually decided, although the part of the UPR pathway that upregulates endoplasmic reticulum chaperones seems to have a protective role during tumour development.
5. In vitro activation of the UPR alters the sensitivity of tumour cells to chemotherapeutic agents.
6. Although several interesting observations have been made to implicate the UPR in tumour growth and resistance to treatments, more comprehensive in vivo studies need to be done to determine how large of a role it has and to identify the most important components of the pathway, and to determine which stages of tumour development are regulated by the UPR.

要点翻译：

1. 当真核细胞遭遇影响内质网蛋白质折叠的不良生理条件时，会激活信号转导级联反应——这一过程被称为未折叠蛋白反应（UPR）。
2. 该反应是一种多管齐下的应对机制，主要发挥细胞保护作用，但在长期应激条件下则会激活凋亡程序。
3. 肿瘤组织因血管化不足可激活UPR通路。这种微环境导致氧气和营养物质匮乏，进而影响分泌途径蛋白的正常成熟。
4. UPR的激活可能促进肿瘤休眠、助力肿瘤生长，或通过诱导凋亡保护宿主。虽然上调内质网分子伴侣的UPR通路在肿瘤发展中似乎具有保护作用，但目前尚不清楚平衡点如何确立，以及肿瘤细胞命运的决定机制。
5. 体外实验表明，UPR的激活会改变肿瘤细胞对化疗药物的敏感性。
6. 尽管已有若干重要发现揭示了UPR在肿瘤生长和治疗耐药性中的作用，但仍需开展更全面的体内研究以确定其影响程度、识别通路关键组分，并明确UPR调控肿瘤发展的具体阶段。

英文摘要：

Having accumulated mutations that overcome cell-cycle and apoptotic checkpoints, the main obstacle to survival faced by a cancer cell is the restricted supply of nutrients and oxygen. These conditions impinge on protein folding in the endoplasmic reticulum and activate a largely cytoprotective signalling pathway called the unfolded protein response. Prolonged activation of this response can, however, terminate in apoptosis. Recent delineation of the components of this response, coupled with several clinical studies, indicate that it is uniquely poised to have a role in regulating the balance between cancer cell death, dormancy and aggressive growth, as well as altering the sensitivity of solid tumours to chemotherapeutic agents.

摘要翻译： 

在积累了能够绕过细胞周期和凋亡检查点的突变之后，癌细胞面临的主要生存障碍是营养和氧气的有限供应。这些条件会影响内质网中的蛋白质折叠，并激活一种被称为“未折叠蛋白反应”的、主要具有细胞保护作用的信号通路。然而，这一反应的长时间激活最终可能导致细胞凋亡。最近对该反应组分的深入研究，以及若干临床研究表明，它在调控癌细胞死亡、休眠与侵袭性生长之间的平衡方面具有独特的作用，并可能改变实体瘤对化疗药物的敏感性。

原文链接：

The role of the unfolded protein response in tumour development: friend or foe?