Han Anna, Liu Jiajing, Du Pan, Li Wenxuan, Quan Haiyan, Lin Zhenhua, Chen Liyan
Central Laboratory, Yanbian University Hospital, Yanji 133000, PR China; Key Laboratory Pathobiology, State Ethnic Affairs Commission, Yanbian University, Yanji 133000, PR China.
Key Laboratory Pathobiology, State Ethnic Affairs Commission, Yanbian University, Yanji 133000, PR China.
Phytomedicine. 2025 Jan;136:156298. doi: 10.1016/j.phymed.2024.156298. Epub 2024 Dec 7.
Pancreatic cancer (PC) is a malignant tumor with complex development mechanisms and a poor prognosis. Taraxasterol (TAX), a pentacyclic triterpenoid plant sterol derived from Taraxacum mongolicum, has multiple biological activities including an anti-tumor effect. However, the mechanism by which TAX exerts its anticancer effects in PC remains unclear.
This study aimed to elucidate the molecular mechanism by which TAX suppresses the proliferation of PC.
The intersection of TAX and PC targets was obtained through network pharmacology. RNA-seq was used to identify TAX-induced differentially expressed genes in PC. Molecular docking, CETSA, western blot analysis, and qRT-PCR were performed to confirm the effectiveness of targets. The influence of TAX on PC was assessed by analyzing proliferation, apoptosis, and the cell cycle via MTT assay, colony formation assay, and flow cytometry, respectively. Co-IP assay and immunofluorescence assay were used to evaluate the effect of TAX on targeted genes. A nude mouse xenograft model was constructed to determine the inhibitory effects of TAX on PC in vivo.
TAX suppressed PC cell proliferation by promoting apoptosis and inducing cell cycle arrest in vitro and in vivo. Mechanistically, TAX interacted with MDM2, a critical regulator of proliferation, and decreased its stability by inducing ubiquitin-mediated degradation, which facilitates the nuclear translocation of p53 and downregulation of CXCL5 transcription, ultimately suppressing PC cell proliferation.
MDM2/p53/CXCL5 is the key pathway of TAX inhibiting the proliferation of PC cells.
胰腺癌（PC）是一种发展机制复杂且预后较差的恶性肿瘤。蒲公英甾醇（TAX）是一种从蒙古蒲公英中提取的五环三萜类植物甾醇，具有多种生物学活性，包括抗肿瘤作用。然而，TAX在PC中发挥抗癌作用的机制仍不清楚。
本研究旨在阐明TAX抑制PC增殖的分子机制。
通过网络药理学获得TAX与PC靶点的交集。利用RNA测序鉴定TAX诱导的PC差异表达基因。进行分子对接、热蛋白质组分析、蛋白质免疫印迹分析和定量逆转录聚合酶链反应以确认靶点有效性。分别通过MTT法、集落形成试验和流式细胞术分析增殖、凋亡和细胞周期，评估TAX对PC的影响。采用免疫共沉淀试验和免疫荧光试验评估TAX对靶向基因的作用。构建裸鼠异种移植模型以确定TAX在体内对PC的抑制作用。
TAX在体外和体内均通过促进凋亡和诱导细胞周期停滞来抑制PC细胞增殖。机制上，TAX与增殖的关键调节因子MDM2相互作用，并通过诱导泛素介导的降解降低其稳定性，这促进了p53的核转位并下调CXCL5转录，最终抑制PC细胞增殖。
MDM2/p53/CXCL5是TAX抑制PC细胞增殖的关键途径。
