Gui Zhenwei, Li Jingwei, Li Juan, Li Xiaoduo, Chen Lihong, Ma Zhengcai, Tang Xiang, Gong Xiaobao, Chai Xue, Lu Fangfang, Li Mengmeng, Ma Hang, Li Xuegang, Ye Xiaoli
Engineering Research Center of Coptis Development & Utilization (Ministry of Education), School of Life Sciences, Southwest University, Chongqing, 400715, China.
School of Pharmaceutical Sciences and Chinese Medicine, Southwest University, Chongqing, 400716, China.
Chem Biol Interact. 2023 Apr 1;374:110408. doi: 10.1016/j.cbi.2023.110408. Epub 2023 Feb 21.
The increasing incidence of colorectal cancer (CRC) has become a major global public health burden. The natural drug Berberine (BBR) has shown potential in preventing CRC, and IGF2 mRNA binding protein 3 (IGF2BP3) may be a target of BBR. This study aims to investigate the mechanisms of BBR acting on IGF2BP3 to improve CRC. The results showed that IGF2BP3 played an important role in the development of CRC. BBR down-regulated IGF2BP3 expression and inhibited CRC growth in mice. Cell thermodynamic stability analysis (CETSA) and drug affinity responsive target stability (DARTS) analysis showed BBR may bind to IGF2BP3. BBR may induce structural changes in IGF2BP3 and decrease its protein stability in cytoplasm. The results from Co-Immunoprecipitation (Co-IP) suggested that BBR promoted the ubiquitination of IGF2BP3 by tripartite motif-containing protein 21 (TRIM21). Through RNA binding protein Immunoprecipitation (RIP) assay, it was found BBR inhibited the stabilization of CDK4/CCND1 mRNA by IGF2BP3 and promoted G1/S phase arrest in CRC cells. Overexpression of IGF2BP3 in vitro and in vivo attenuated the inhibition of CRC growth by BBR. This work demonstrated the potential of BBR targeting to IGF2BP3 in improving CRC and provided a new strategy for clinical treatment on CRC as well as novel anticancer drug design based on IGF2BP3 and TRIM21.
结直肠癌（CRC）发病率的不断上升已成为全球主要的公共卫生负担。天然药物黄连素（BBR）在预防CRC方面显示出潜力，胰岛素样生长因子2信使核糖核酸结合蛋白3（IGF2BP3）可能是BBR的一个靶点。本研究旨在探讨BBR作用于IGF2BP3改善CRC的机制。结果表明，IGF2BP3在CRC的发生发展中起重要作用。BBR下调IGF2BP3表达并抑制小鼠CRC生长。细胞热稳定性分析（CETSA）和药物亲和力响应靶点稳定性（DARTS）分析表明BBR可能与IGF2BP3结合。BBR可能诱导IGF2BP3的结构变化并降低其在细胞质中的蛋白质稳定性。免疫共沉淀（Co-IP）结果表明，BBR通过含三联基序蛋白21（TRIM21）促进IGF2BP3的泛素化。通过RNA结合蛋白免疫沉淀（RIP）试验发现，BBR抑制IGF2BP3对细胞周期蛋白依赖性激酶4/细胞周期蛋白D1（CDK4/CCND1）信使核糖核酸的稳定作用，并促进CRC细胞的G1/S期阻滞。体外和体内过表达IGF2BP3减弱了BBR对CRC生长的抑制作用。这项工作证明了BBR靶向IGF2BP3改善CRC的潜力，并为CRC的临床治疗以及基于IGF2BP3和TRIM21的新型抗癌药物设计提供了新策略。
