文章：

蛋白酶体：一种合适的抗肿瘤靶点

The proteasome: a suitable antineoplastic target

原文发布日期：2004-05-01

DOI: 10.1038/nrc1361

类型: Review Article

开放获取: 否

要点：

1. The proteasome is an abundant, catalytic complex that is found in both the nucleus and cytoplasm of eukaryotic cells.
2. The function of the proteasome is to degrade or process intracellular proteins, some of which represent mediators of cell-cycle progression and apoptosis, such as the cyclins, caspases, BCL2 and nuclear factor of κB (NF-κB).
3. Malignant cells are more susceptible to certain proteasome inhibitors, which might be explained, in part, by the reversal or bypass of some of the effects of the mutations in cell-cycle and apoptotic checkpoints that have led to tumorigenesis.
4. Other explanations for this differential susceptibility include higher dependency of highly proliferative malignant cells on the proteasome system to remove aberrant proteins and the dependence of some tumours on the proteasome-dependent NF-κB activation pathway to maintain drug or radiation resistance.
5. In addition to direct apoptotic effects, there is a strong biological basis for using proteasome inhibition to enhance sensitivity to standard chemotherapy and radiation therapy, and to overcome drug resistance.
6. The proteasome inhibitor bortezomib has established clinical efficacy and an approved clinical indication for the treatment of relapsed and refractory multiple myeloma — proof of the principle that the proteasome is a suitable antineoplastic target.

要点翻译：

1. 蛋白酶体是一种含量丰富的催化复合物，存在于真核细胞的细胞核与细胞质中。
2. 其功能是降解或处理细胞内蛋白质，其中一些蛋白质是细胞周期进程和凋亡的介导因子，如细胞周期蛋白、半胱天冬酶、BCL2以及核因子κB（NF-κB）。
3. 恶性细胞对某些蛋白酶体抑制剂更为敏感，部分原因可能是这些抑制剂能够逆转或绕过导致肿瘤发生的细胞周期和凋亡检查点中的某些突变效应。
4. 这种差异性敏感性的其他解释包括：高增殖性恶性细胞更依赖蛋白酶体系统清除异常蛋白质，以及某些肿瘤依赖蛋白酶体激活的NF-κB通路来维持对药物或放射的抵抗性。
5. 除直接诱导凋亡作用外，蛋白酶体抑制剂在增强对标准化疗和放射治疗的敏感性以及克服耐药性方面具有坚实的生物学基础。
6. 蛋白酶体抑制剂硼替佐米已被证实具有临床疗效，并获批准用于治疗复发性和难治性多发性骨髓瘤——这证明了蛋白酶体可作为合适的抗肿瘤靶点这一原则。

英文摘要：

The proteasome is an abundant multi-enzyme complex that provides the main pathway for degradation of intracellular proteins in eukaryotic cells. As such, it controls the levels of proteins that are important for cell-cycle progression and apoptosis in normal and malignant cells; for example, cyclins, caspases, BCL2 and nuclear factor of κB. A proteasome inhibitor — bortezomib — has been developed that has shown efficacy as an anticancer agent in the clinic. How can targeting such a universal, broadly active cellular component provide the selectivity and specificity that are required for cancer therapeutics?

摘要翻译： 

异体骨髓细胞和外周血干细胞治愈白血病的能力，仍是人类免疫系统识别并摧毁肿瘤最引人注目的例证。然而，如何在不引发移植物抗宿主病的前提下，利用这种“移植物抗白血病”效应来改善晚期患者的预后，一直是关键难题。近期发现白血病细胞特异性表达、且可被T细胞识别的分子，表明免疫反应可以被精准导向。这种T细胞的抗癌特异性即将被常规纳入异体干细胞移植方案，以促进肿瘤清除。

原文链接：

The proteasome: a suitable antineoplastic target