University of Illinois at Chicago, Department of Medicine, 840 S. Wood St., Room 1041, Chicago, IL 60612, USA.
Expert Opin Investig Drugs. 2010 Feb;19(2):235-42. doi: 10.1517/13543780903563364.
The proteasome is responsible for ubiquitin- and ATP-dependent proteolysis of cellular proteins. The latest advances in proteasome studies led to the development of proteasome inhibitors as drugs against human cancer. It has been shown that proteasome inhibitors selectively kill cancer, but not normal cells. However, the exact mechanisms of the anticancer activity of proteasome inhibitors are not well understood. The oncogenic transcription factor Forkhead Box M1 (FoxM1) is overexpressed in a majority of human carcinomas, while its expression is usually low in normal cells. In addition, FoxM1 may also drive tumor invasion, angiogenesis and metastasis. For these reasons, FoxM1 is an attractive target for anticancer drugs.
My aim is to discuss recent publications that point out novel mechanism of action of proteasome inhibitors. In addition, I describe the identification of new types of proteasome inhibitors, called thiazole antibiotics. Using a cell-based screening system, the thiazole antibiotics siomycin A and thiostrepton were isolated as inhibitors of FoxM1 transcriptional activity and expression. Paradoxically, it has been shown that these drugs also stabilize the expression of other proteins and act as proteasome inhibitors in vitro. Moreover, it was found that well-known proteasome inhibitors, such as MG115, MG132 and bortezomib, inhibit FoxM1 transcriptional activity and FoxM1 expression.
It has been shown that proteasome inhibitors suppress FoxM1 expression and simultaneously induce apoptosis in human tumor cell lines. This review describes the correlation between negative regulation of FoxM1 by proteasome inhibitors and apoptosis, and suggests that negative regulation of FoxM1 is a universal feature of these drugs and may contribute to their anticancer activity.
Oncogenic transcription factor FoxM1 is upregulated in a majority of human cancers, suggesting that growth of cancer cells may depend on FoxM1 activity. A short time ago, it has been shown that proteasome inhibitors simultaneously inhibit FoxM1 expression and induce apoptosis in human cancer cells. This effect may explain specificity of proteasome inhibitors to induce apoptosis in cancer, but not in normal cells. Now, it is critical to determine the role of suppression of FoxM1 in apoptosis induced by proteasome inhibitors and to establish how significant the inhibition of FoxM1 is for the anticancer activity of proteasome inhibitors.
蛋白酶体负责细胞蛋白的泛素和 ATP 依赖性降解。蛋白酶体研究的最新进展导致了蛋白酶体抑制剂作为抗癌药物的发展。已经表明，蛋白酶体抑制剂选择性地杀死癌症，但不杀死正常细胞。然而，蛋白酶体抑制剂抗癌活性的确切机制尚不清楚。致癌转录因子叉头盒 M1（FoxM1）在大多数人类癌中过度表达，而在正常细胞中其表达通常较低。此外，FoxM1 还可能驱动肿瘤侵袭、血管生成和转移。出于这些原因，FoxM1 是抗癌药物的一个有吸引力的靶点。
我的目的是讨论指出蛋白酶体抑制剂新作用机制的最新出版物。此外，我还描述了新型蛋白酶体抑制剂——噻唑抗生素的鉴定。使用基于细胞的筛选系统，噻唑抗生素硅霉素 A 和硫链丝菌素被分离为 FoxM1 转录活性和表达的抑制剂。矛盾的是，已经表明这些药物还稳定其他蛋白质的表达，并在体外作为蛋白酶体抑制剂发挥作用。此外，发现众所周知的蛋白酶体抑制剂，如 MG115、MG132 和硼替佐米，抑制 FoxM1 转录活性和 FoxM1 表达。
已经表明，蛋白酶体抑制剂抑制 FoxM1 表达并同时诱导人肿瘤细胞系凋亡。本篇综述描述了蛋白酶体抑制剂对 FoxM1 的负调控与凋亡之间的相关性，并表明 FoxM1 的负调控是这些药物的普遍特征，可能有助于它们的抗癌活性。
致癌转录因子 FoxM1 在大多数人类癌症中上调，表明癌细胞的生长可能依赖于 FoxM1 活性。不久前，已经表明蛋白酶体抑制剂同时抑制 FoxM1 表达并诱导人癌细胞凋亡。这种作用可能解释了蛋白酶体抑制剂在诱导癌症而非正常细胞凋亡方面的特异性。现在，确定蛋白酶体抑制剂诱导凋亡中 FoxM1 抑制的作用以及确定 FoxM1 抑制对蛋白酶体抑制剂抗癌活性的重要性至关重要。
