Wu Lipeng, Yu Meng, Liang Huosheng, Lin Long, Li Huajian, Chen Guangyang, Muhetaer Halimulati, Li Jingjing, Wu Bo, Jia Xuejing, Dang Yuanye, Zheng Guodong, Li Chuwen
Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University, Guangzhou 510645, China.
School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China.
Curr Issues Mol Biol. 2025 Feb 27;47(3):155. doi: 10.3390/cimb47030155.
Non-small cell lung cancer (NSCLC) remains one of the most significant contributors to cancer-related mortality. This investigation explores the influence and underlying mechanisms of the USP1 inhibitor SJB2-043 on A549 cells, with the aim of advancing the development of anti-NSCLC therapeutics.
Publicly available databases were utilized to assess USP1 expression and its association with the progression of NSCLC. Gene expression variations were ascertained through RNA sequencing, followed by the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology pathway enrichment evaluations. Various doses of SJB2-043 were administered to A549 cells to evaluate its impact on cell multiplication, motility, apoptosis, and the cell cycle using CCK-8 assays, colony formation, wound healing, flow cytometry, and Western blotting (WB).
USP1 was found to be overexpressed in NSCLC specimens and linked to adverse prognosis. Treatment with SJB2-043 markedly inhibited A549 cell proliferation and migration, diminished clonogenic potential, and triggered apoptosis in a dose-dependent manner. Modifications in the cell cycle were observed, showing an elevated percentage of cells in the G2 phase while exhibiting a parallel decline in the G phase. WB examination demonstrated diminished protein levels of N-cadherin, CyclinB, CDK1, C-myc, Bcl-2, p-ERK/ERK, p-p38/p38, p-JNK/JNK, p-AKT/AKT, and p-mTOR/mTOR, alongside an upregulation of E-cadherin, ZO-1, occludin, p53, Bax, p-β-catenin/β-catenin, and GSK3β.
SJB2-043 exerts a suppressive effect on A549 cell proliferation, migration, and epithelial-mesenchymal transition while enhancing apoptosis. These cellular effects appear to be mediated through the inhibition of the MAPK, Wnt/β-catenin, and PI3K/AKT/mTOR signaling cascades, in addition to modulation of the cell cycle.
非小细胞肺癌（NSCLC）仍然是癌症相关死亡的主要原因之一。本研究探讨USP1抑制剂SJB2-043对A549细胞的影响及其潜在机制，旨在推动抗NSCLC治疗药物的开发。
利用公开可用的数据库评估USP1表达及其与NSCLC进展的关联。通过RNA测序确定基因表达变化，随后进行京都基因与基因组百科全书（KEGG）和基因本体论（GO）通路富集评估。将不同剂量的SJB2-043施用于A549细胞，使用CCK-8测定、集落形成、伤口愈合、流式细胞术和蛋白质免疫印迹法（WB）评估其对细胞增殖、运动、凋亡和细胞周期的影响。
发现USP1在NSCLC标本中过表达，并与不良预后相关。用SJB2-043处理显著抑制A549细胞增殖和迁移，降低克隆形成潜力，并以剂量依赖性方式诱导凋亡。观察到细胞周期发生改变，G2期细胞百分比升高，而G1期细胞百分比相应下降。WB检测显示N-钙黏蛋白、细胞周期蛋白B、细胞周期蛋白依赖性激酶1（CDK1）、C- myc、Bcl-2、磷酸化细胞外信号调节激酶/细胞外信号调节激酶（p-ERK/ERK）、磷酸化p38丝裂原活化蛋白激酶/p38丝裂原活化蛋白激酶（p-p38/p38）、磷酸化c-Jun氨基末端激酶/c-Jun氨基末端激酶（p-JNK/JNK）、磷酸化蛋白激酶B/蛋白激酶B（p-AKT/AKT）和磷酸化哺乳动物雷帕霉素靶蛋白/哺乳动物雷帕霉素靶蛋白（p-mTOR/mTOR）的蛋白水平降低，同时E-钙黏蛋白、紧密连接蛋白1（ZO-1）、闭合蛋白、p53、Bax、磷酸化β-连环蛋白/β-连环蛋白（p-β-catenin/β-catenin）和糖原合成酶激酶3β（GSK3β）上调。
SJB2-043对A549细胞的增殖、迁移和上皮-间质转化具有抑制作用，同时增强细胞凋亡。这些细胞效应似乎是通过抑制丝裂原活化蛋白激酶（MAPK）、Wnt/β-连环蛋白和磷脂酰肌醇-3-激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白（PI3K/AKT/mTOR）信号级联反应以及调节细胞周期介导的。
