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Tropomodulin 3 Overexpression as a Marker for Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
Triptolide targets JUN to reverse cisplatin resistance of ovarian cancer: insights from single-cell transcriptome
Chen Wang1, Junfeng Guo1, Taiyang Ye2
1Department of Traditional Chinese Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Background:
Platinum-resistant ovarian cancer (PROC) is a major clinical challenge driven by profound intratumoral heterogeneity. Triptolide (TP) exhibits promising anti-tumor potential, yet its precise mechanisms within PROC remain elusive due to the limitations of traditional target-screening strategies.
Methods:
This study developed a comprehensive strategy integrating computational predictions with in vitro experimental validations. First, scRNA-seq data were processed to evaluate TP target genes predicted by SwissTargetPrediction, alongside pseudotime trajectory and CellChat intercellular communication analyses. Subsequently, an ensemble of six machine learning (ML) algorithms (LASSO, Random Forest, Boruta, Decision Tree, XGBoost, and GBM) was utilized to pinpoint the core therapeutic target. To verify direct molecular engagement, molecular docking, molecular dynamics (MD) simulations, and Surface Plasmon Resonance (SPR) assays were performed. Finally, the functional mechanism of the identified target in CDDP resistance was validated in vitro using parental SKOV3 and resistant SKOV3/CDDP cell lines.
Results:
scRNA-seq analysis revealed TP target genes are preferentially enriched in highly genomically unstable malignant epithelial cells. This subpopulation showed an aggressive intercellular communication profile, profound dependence on extracellular matrix (ECM) signals, and dominant secretion of the chemoresistance-related cytokine osteopontin (SPP1). Furthermore, the ML pipeline consistently pinpointed the proto-oncogene JUN as the core therapeutic target. Experiments confirmed TP efficiently suppressed aberrant c-Jun overexpression. Targeted JUN knockdown restored CDDP sensitivity, while its overexpression antagonized the synergistic cytotoxic and apoptotic effects of TP and CDDP. Ultimately, TP reverses CDDP resistance in PROC by downregulating JUN, dismantling intracellular pro-survival networks, and disrupting pro-tumorigenic crosstalk.
Conclusion:
In conclusion, TP reverses CDDP resistance in PROC by downregulating JUN, which dismantles intracellular pro-survival networks. Integrating scRNA-seq and ML provides an accurate paradigm for deciphering botanical pharmacology, laying a strong foundation for the future development of TP-based therapies tailored for PROC.
Insights
Triptolide (TP) reverses platinum-resistant ovarian cancer (PROC) chemoresistance by targeting the proto-oncogene JUN. This study integrates scRNA-seq and machine learning to reveal TP
Area of Science:
- Oncology
- Pharmacology
- Genomics
Background:
- Platinum-resistant ovarian cancer (PROC) presents a significant clinical challenge due to tumor heterogeneity.
- Triptolide (TP) shows anti-tumor potential, but its mechanisms in PROC are unclear.
- Traditional target-screening methods are limited for complex diseases like PROC.
Purpose of the Study:
- To elucidate the molecular mechanisms of Triptolide (TP) in overcoming platinum-resistant ovarian cancer (PROC).
- To identify the core therapeutic target of TP in PROC using an integrated computational and experimental approach.
- To validate the role of the identified target in chemoresistance and its modulation by TP.
Main Methods:
- Integrated single-cell RNA sequencing (scRNA-seq) with computational predictions (SwissTargetPrediction, pseudotime, CellChat).
- Employed an ensemble of six machine learning (ML) algorithms to pinpoint the core therapeutic target.
- Validated direct molecular engagement using molecular docking, MD simulations, and SPR assays.
- Confirmed functional mechanisms in vitro using SKOV3 and SKOV3/CDDP cell lines.
Main Results:
- TP target genes were enriched in aggressive malignant epithelial cells with high genomic instability.
- Machine learning consistently identified the proto-oncogene JUN as the core therapeutic target.
- TP suppressed c-Jun overexpression, and JUN knockdown restored CDDP sensitivity.
- TP reverses CDDP resistance by downregulating JUN, disrupting pro-survival networks and crosstalk.
Conclusions:
- Triptolide (TP) reverses CDDP resistance in PROC by downregulating JUN, dismantling pro-survival networks.
- The integration of scRNA-seq and ML offers a robust paradigm for botanical pharmacology research.
- This study provides a foundation for developing novel TP-based therapies for PROC.
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