Targeting the ubiquitin-proteasome pathway in breast cancer.
Targeting the ubiquitin-proteasome pathway in breast cancer.
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DOI：
10.3816/cbc.2004.n.020
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发表时间：
2004-06-01
影响因子：
3.1
通讯作者：
Durbecq, Virginie
中科院分区：
文献类型：
--
作者：
Cardoso, Fatima;Ross, Jeffrey S;Durbecq, Virginie
26 S蛋白酶体是一种腺苷三磷酸依赖性多催化蛋白酶，负责大多数非溶酶体细胞内蛋白质降解。为了被选择用于蛋白酶体降解，蛋白质必须预先用多聚泛素链标记，然后被蛋白酶体识别;泛素链被异肽酶去除，蛋白质被水解成小多肽。除了去除受损/不必要的蛋白质外，蛋白酶体也是调节一些关键调节蛋白及其抑制剂的重要机制。这种调节对于许多细胞过程的控制至关重要，包括转录因子的激活、细胞周期进程和凋亡。泛素-蛋白酶体途径在肿瘤细胞中的关键作用导致了对蛋白酶体抑制作为潜在的抗癌疗法的研究。二肽硼酸类似物硼替佐米，以前称为PS-341，是一种有效的，高选择性和可逆的蛋白酶体抑制剂。作为第一种用于临床的此类药物，它最近已被美国食品和药物管理局批准用于治疗复发性和难治性多发性骨髓瘤，目前正在临床试验中测试用于治疗各种恶性肿瘤。本文总结了泛素-蛋白酶体通路的生物学，回顾了蛋白酶体抑制作为乳腺癌治疗策略的临床前和临床数据，并讨论了未来涉及硼替佐米的联合治疗方案。
The 26S proteasome is an adenosine triphosphate-dependent multicatalytic protease that is responsible for most nonlysosomal intracellular protein degradation. To be selected for proteasomal degradation, proteins must be previously tagged with a polyubiquitin chain, which is then recognized by the proteasome; the ubiquitin chain is removed by isopeptidases and the protein is hydrolysed to small polypeptides. In addition to removing damaged/unnecessary proteins, the proteasome is also an important mechanism of regulation of some key regulatory proteins and their inhibitors. This regulation is crucial for the control of many cellular processes, including activation of transcription factors, cell cycle progression, and apoptosis. The critical role of the ubiquitin-proteasome pathway in tumor cells has led to the investigation of proteasome inhibition as a potential anticancer therapy. The dipeptide boronic acid analogue bortezomib, formerly known as PS-341, is a potent, highly selective, and reversible proteasome inhibitor. The first drug of this class to be used in the clinical setting, it has recently been approved by the US Food and Drug Administration for the treatment of relapsed and refractory multiple myeloma and is currently being tested in clinical trials for the treatment of a wide variety of malignancies. This article provides a summary of the biology of the ubiquitin-proteasome pathway, reviews the available preclinical and clinical data of proteasome inhibition as a therapeutic strategy in breast cancer, and discusses future combination regimens involving bortezomib.