Gong Huiyuan, Yang Xiaomin, An Lijun, Zhang Wangming, Liu Xiaohua, Shu Liping, Yang Liuqi
Department of Immunology, Basic Medical College, Guizhou Medical University, No.6, Ankang Road, Guian New District, Guiyang, 550004, Guizhou, People's Republic of China.
Mol Cell Biochem. 2025 Jan;480(1):521-533. doi: 10.1007/s11010-024-04977-3. Epub 2024 Mar 29.
Proprotein convertase subtilisin/kexin type 5 (PCSK5) is a member of the proprotein convertase (PC) family, which processes immature proteins into functional proteins and plays an important role in the process of cell migration and transformation. Andrographolide is a non-peptide compound with PC inhibition and antitumor activity. Our research aimed to investigate the functional role of PCSK5 downregulation combined with Andro on GBM progression. Results from the cancer genome atlas (TCGA) and clinical samples revealed a significant upregulation of PCSK5 in GBM tissues than in non-tumor brain tissues. Higher expression of PCSK5 was correlated with advanced GBM stages and worse patient prognosis. PCSK5 knockdown attenuated the epithelial-mesenchymal transition (EMT)-like properties of GBM cells induced by IL-6. PCSK5 knockdown in combination with Andro treatment significantly inhibited the proliferation and invasion of GBM cells in vitro, as well as tumor growth in vivo. Mechanistically, PCSK5 downregulation reduced the expression of p-STAT3 and Matrix metalloproteinases (MMPs), which could be rescued by the p-STAT3 agonist. STAT3 silencing downregulated the expression of MMPs without affecting PCSK5. Furthermore, Andro in combination with PCSK5 silencing significantly inhibited STAT3/MMPs axis. These observations provided evidence that PCSK5 functioned as a potential tumor promoter by regulating p-STAT3/MMPs and the combination of Andro with PCSK5 silencing might be a good strategy to prevent GBM progression.
前蛋白转化酶枯草杆菌蛋白酶/kexin 5型（PCSK5）是前蛋白转化酶（PC）家族的成员，该家族将未成熟蛋白质加工成功能性蛋白质，并在细胞迁移和转化过程中发挥重要作用。穿心莲内酯是一种具有PC抑制和抗肿瘤活性的非肽化合物。我们的研究旨在探讨下调PCSK5联合穿心莲内酯对胶质母细胞瘤（GBM）进展的功能作用。癌症基因组图谱（TCGA）和临床样本的结果显示，与非肿瘤脑组织相比，GBM组织中PCSK5显著上调。PCSK5的高表达与GBM的晚期阶段和患者较差的预后相关。敲低PCSK5可减弱IL-6诱导的GBM细胞的上皮-间质转化（EMT）样特性。敲低PCSK5联合穿心莲内酯处理在体外显著抑制GBM细胞的增殖和侵袭，以及体内肿瘤生长。机制上，下调PCSK5可降低p-STAT3和基质金属蛋白酶（MMPs）的表达，而p-STAT3激动剂可使其恢复。沉默STAT3可下调MMPs的表达而不影响PCSK5。此外，穿心莲内酯联合沉默PCSK5可显著抑制STAT3/MMPs轴。这些观察结果提供了证据，表明PCSK5通过调节p-STAT3/MMPs发挥潜在的肿瘤促进作用，穿心莲内酯与沉默PCSK5的联合应用可能是预防GBM进展的良好策略。
