Department of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of Korea.
Team of Radiation Convergence Research, Korea Institute of Radiological & Medical Sciences, Seoul 01812, Republic of Korea.
Int J Mol Sci. 2023 May 8;24(9):8441. doi: 10.3390/ijms24098441.
Changes in the DNA damage response (DDR) and cellular metabolism are two important factors that allow cancer cells to proliferate. DDR is a set of events in which DNA damage is recognized, DNA repair factors are recruited to the site of damage, the lesion is repaired, and cellular responses associated with the damage are processed. In cancer, DDR is commonly dysregulated, and the enzymes associated with DDR are prone to changes in ubiquitination. Additionally, cellular metabolism, especially glycolysis, is upregulated in cancer cells, and enzymes in this metabolic pathway are modulated by ubiquitination. The ubiquitin-proteasome system (UPS), particularly E3 ligases, act as a bridge between cellular metabolism and DDR since they regulate the enzymes associated with the two processes. Hence, the E3 ligases with high substrate specificity are considered potential therapeutic targets for treating cancer. A number of small molecule inhibitors designed to target different components of the UPS have been developed, and several have been tested in clinical trials for human use. In this review, we discuss the role of ubiquitination on overall cellular metabolism and DDR and confirm the link between them through the E3 ligases NEDD4, APC/C, FBXW7, and Pellino1. In addition, we present an overview of the clinically important small molecule inhibitors and implications for their practical use.
DNA 损伤反应 (DDR) 和细胞代谢的变化是允许癌细胞增殖的两个重要因素。DDR 是一组事件，其中包括识别 DNA 损伤、募集 DNA 修复因子到损伤部位、修复损伤以及处理与损伤相关的细胞反应。在癌症中，DDR 通常失调，与 DDR 相关的酶易发生泛素化改变。此外，癌细胞中的细胞代谢，特别是糖酵解，被上调，该代谢途径中的酶受泛素化调节。泛素-蛋白酶体系统 (UPS)，特别是 E3 连接酶，作为细胞代谢和 DDR 之间的桥梁，因为它们调节与这两个过程相关的酶。因此，具有高底物特异性的 E3 连接酶被认为是治疗癌症的潜在治疗靶点。已经开发了许多旨在针对 UPS 不同成分的小分子抑制剂，并且已经在临床试验中测试了几种用于人体的抑制剂。在这篇综述中，我们讨论了泛素化在整体细胞代谢和 DDR 中的作用，并通过 E3 连接酶 NEDD4、APC/C、FBXW7 和 Pellino1 证实了它们之间的联系。此外，我们还概述了临床上重要的小分子抑制剂及其实际应用的意义。
