Deng Yuanfei, Yu Cuifu, Chen Lushi, Zhang Xin, Lei Qiucheng, Liu Qing, Cai Gengxi, Liu Fang
Department of Pathology, The First People's Hospital of Foshan, Foshan, China.
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China.
Front Pharmacol. 2022 May 4;13:858901. doi: 10.3389/fphar.2022.858901. eCollection 2022.
Hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer with limited treatment options and extremely poor prognosis worldwide. Recently, the proteolysis targeting chimeras (PROTACs), which aim to induce proteasome-mediated degradation of interesting proteins via recruiting E3 ligases, have become the advanced tools and attractive molecules for cancer treatment. However, the anticancer effects of PROTACs in HCC remain to be clarified. Here, we evaluate the anticancer activity of ARV-771, a previously reported PROTAC compound designed for bromodomain and extra-terminal domain (BET) proteins, in HCC. We show that ARV-771 suppresses the cell viability and colony formation of HCC cells via arresting cell cycle progression and triggering apoptosis. Further investigations reveal that ARV-771 notably downregulates multiple non-proteasomal deubiquitinases which are critical to the development of cancers. Additionally, HCC cells can decrease their sensitivity to ARV-771 via activating the MEK/ERK and p38 MAPKs. ARV-771 also inhibits HCC progression . Moreover, we show that ARV-771 and sorafenib, a Raf inhibitor that clinically used for targeted therapy of liver cancer, can synergistically inhibit the growth of HCC cells. Overall, this study not only explores the anticancer activity of ARV-771 and its underlying mechanisms in HCC, but also deepens our understanding of deubiquitinases, MAPKs, cell cycle, and apoptosis induction in cancer therapy.
肝细胞癌（HCC）是最常被诊断出的肝癌，在全球范围内治疗选择有限且预后极差。最近，靶向蛋白水解嵌合体（PROTACs）旨在通过招募E3连接酶诱导蛋白酶体介导的目标蛋白降解，已成为癌症治疗的先进工具和有吸引力的分子。然而，PROTACs在HCC中的抗癌作用仍有待阐明。在此，我们评估了ARV-771（一种先前报道的针对溴结构域和额外末端结构域（BET）蛋白设计的PROTAC化合物）在HCC中的抗癌活性。我们发现ARV-771通过阻滞细胞周期进程和触发凋亡来抑制HCC细胞的活力和集落形成。进一步研究表明，ARV-771显著下调多种对癌症发展至关重要的非蛋白酶体去泛素化酶。此外，HCC细胞可通过激活MEK/ERK和p38丝裂原活化蛋白激酶（MAPKs）来降低其对ARV-771的敏感性。ARV-771还抑制HCC进展。此外，我们表明ARV-771和索拉非尼（一种临床上用于肝癌靶向治疗的Raf抑制剂）可协同抑制HCC细胞的生长。总体而言，本研究不仅探索了ARV-771在HCC中的抗癌活性及其潜在机制，还加深了我们对癌症治疗中去泛素化酶、MAPKs、细胞周期和凋亡诱导的理解。
