Ding Ling, Chen Wutao, Luo Cenxin, Weygant Nathaniel, Lai Yi, Ru Dan, Liu Hengan, Wang You, Li He
Traditional Chinese Medicine Department, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
Department of Obstetrics and Gynecology, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
Chin Med. 2025 Aug 6;20(1):122. doi: 10.1186/s13020-025-01174-2.
Triptolide, the active compound of Tripterygium wilfordii, exhibits broad anti-tumor activity. This study explores PPP2CA dysregulation in ovarian cancer (OC) progression via lactate production and evaluates Triptolide's potential to regulate this process.
We used patient-derived xenograft (PDX) models, cell proliferation, and migration assays to assess lactate's impact on OC progression. CRISPR-Cas9 was applied to knock out PPP2CA, examining its effect on lactate production and tumor progression. RNA-seq analyzed transcriptomic changes post-PPP2CA knockout. The PPP2CA-ITGA5 axis was validated using xenografts, immunofluorescence, immunohistochemistry staining and western blot. Exosome isolation and co-culture experiments with tumor cells and human peritoneal mesothelial cells (HPMCs) investigated ITGA5's role in migration. Finally, patient-derived organoids, xenograft tumor model, and lactate assays assessed Triptolide's reversal effect on PPP2CA dysregulation-driven OC progression.
We found that PPP2CA dysregulation significantly promotes OC proliferation, migration, and tumorigenesis by enhancing YAP nuclear translocation and upregulating ITGA5/ITGB1. PPP2CA dysregulation led to ITGA5 upregulation, where ITGA5, as part of the integrin α5β1 heterodimer, plays a key role in driving OC migration. Exosomal ITGA5 facilitates OC metastasis to the HPMCs. Triptolide effectively inhibited patient-derived organoid growth and reduced lactate production in OC cells. By suppressing ITGA5, Triptolide reversed cancer progression and restored tumor-suppressive effects in a PPP2CA-knockout xenograft model.
Our study reveals that Triptolide effectively inhibits OC progression by targeting the PPP2CA-ITGA5 axis, mitigating lactate-driven metabolic reprogramming.
雷公藤甲素是雷公藤的活性成分，具有广泛的抗肿瘤活性。本研究通过乳酸生成探讨PPP2CA失调在卵巢癌（OC）进展中的作用，并评估雷公藤甲素调节这一过程的潜力。
我们使用患者来源的异种移植（PDX）模型、细胞增殖和迁移试验来评估乳酸对OC进展的影响。应用CRISPR-Cas9敲除PPP2CA，检测其对乳酸生成和肿瘤进展的影响。RNA测序分析PPP2CA敲除后的转录组变化。通过异种移植、免疫荧光、免疫组织化学染色和蛋白质印迹验证PPP2CA-ITGA5轴。通过外泌体分离以及肿瘤细胞与人类腹膜间皮细胞（HPMC）的共培养实验，研究ITGA5在迁移中的作用。最后，利用患者来源的类器官、异种移植肿瘤模型和乳酸试验评估雷公藤甲素对PPP2CA失调驱动的OC进展的逆转作用。
我们发现，PPP2CA失调通过增强YAP核转位和上调ITGA5/ITGB1，显著促进OC增殖、迁移和肿瘤发生。PPP2CA失调导致ITGA5上调，其中ITGA5作为整合素α5β1异二聚体的一部分，在驱动OC迁移中起关键作用。外泌体ITGA5促进OC向HPMC转移。雷公藤甲素有效抑制患者来源的类器官生长，并降低OC细胞中的乳酸生成。通过抑制ITGA5，雷公藤甲素在PPP2CA敲除的异种移植模型中逆转了癌症进展并恢复了肿瘤抑制作用。
我们的研究表明，雷公藤甲素通过靶向PPP2CA-ITGA5轴有效抑制OC进展，减轻乳酸驱动的代谢重编程。
