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Triptolide targets PPP2CA/ITGA5 axis to suppress lactate-driven ovarian cancer progression
Ling Ding1, Wutao Chen2,3, Cenxin Luo4
1Traditional Chinese Medicine Department, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
Our study reveals that Triptolide effectively inhibits OC progression by targeting the PPP2CA-ITGA5 axis, mitigating lactate-driven metabolic reprogramming.
Insights
Triptolide inhibits ovarian cancer progression by targeting the PPP2CA-ITGA5 pathway, reducing lactate production and metastasis. This natural compound offers a potential therapeutic strategy for ovarian cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Triptolide, derived from Tripterygium wilfordii, shows anti-tumor potential.
- Ovarian cancer (OC) progression is linked to dysregulation of PPP2CA and increased lactate production.
Purpose of the Study:
- To investigate the role of PPP2CA dysregulation in OC progression through lactate production.
- To evaluate Triptolide's efficacy in modulating this pathway and its therapeutic potential in OC.
Main Methods:
- Utilized patient-derived xenograft (PDX) models, cell assays, and CRISPR-Cas9 for PPP2CA knockout.
- Analyzed transcriptomic changes via RNA-seq and validated the PPP2CA-ITGA5 axis using molecular techniques.
- Assessed Triptolide's effects on organoids, xenografts, and lactate production.
Main Results:
- PPP2CA dysregulation promotes OC proliferation and migration via YAP and the ITGA5/ITGB1 axis.
- Exosomal ITGA5 contributes to OC metastasis to human peritoneal mesothelial cells (HPMCs).
- Triptolide inhibited OC growth, reduced lactate, suppressed ITGA5, and reversed cancer progression in vivo.
Conclusions:
- Triptolide effectively targets the PPP2CA-ITGA5 axis to inhibit OC progression.
- Triptolide mitigates OC metabolic reprogramming driven by lactate production.
- The findings highlight Triptolide as a promising agent for ovarian cancer therapy.
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