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Mefloquine Suppresses Metastasis in Renal Cell Carcinoma Through Targeting SPC25
Yongbo Wang1, He Wang2, Yipeng Xu3,4
1Cixi Biomedical Research Institute, Wenzhou Medical University, Wenzhou, China.
Abstract:
Renal cell carcinoma (RCC) is the third most common malignant tumor in the urinary system, often presenting with distant metastases at diagnosis. Approximately one-quarter of patients undergoing nephrectomy experience distant recurrence. Despite the recent advancements in combination-targeted and immune checkpoint inhibitor therapies, the development of new therapeutic strategies and the identification of biomarkers for metastatic risk remain crucial. The study found that high SPC25 expression is closely associated with poor clinical outcomes, and knocking down SPC25 significantly inhibits tumor cell proliferation and migration. Non-targeted metabolomics analysis also revealed that SPC25 knockdown reduces tumor cell activity, resulting in a low-invasive state. Additionally, this study utilized high-throughput molecular docking to screen small molecule drugs targeting SPC25, aiming to find drugs that inhibit RCC metastasis. The research discovered that mefloquine, at concentrations that do not significantly kill tumor cells, can markedly inhibit RCC metastasis. It was the first to report that mefloquine achieves its anti-metastatic effects by binding to SPC25 and inhibiting epithelial-mesenchymal transition. These results suggest that SPC25 has the potential to serve as an early biomarker for metastatic risk in RCC and highlight a novel strategy where mefloquine inhibits RCC metastasis through SPC25 binding, offering new avenues to improve the prognosis of RCC patients.
Insights
High SPC25 expression predicts poor outcomes in renal cell carcinoma (RCC). Mefloquine inhibits RCC metastasis by targeting SPC25, offering a new therapeutic strategy for this common urinary system cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Renal cell carcinoma (RCC) is a significant urinary system malignancy, frequently diagnosed with distant metastases.
- A substantial proportion of patients experience recurrence post-nephrectomy, necessitating improved therapeutic strategies and metastatic risk biomarkers.
- Current treatments, including targeted therapies and immune checkpoint inhibitors, show promise but do not fully address metastatic progression.
Purpose of the Study:
- To investigate the role of SPC25 in renal cell carcinoma (RCC) progression and metastatic potential.
- To identify potential therapeutic agents targeting SPC25 for the inhibition of RCC metastasis.
- To explore the mechanism by which identified agents exert anti-metastatic effects.
Main Methods:
- Correlation analysis of SPC25 expression with clinical outcomes in RCC patients.
- In vitro studies involving SPC25 knockdown to assess effects on tumor cell proliferation and migration.
- Non-targeted metabolomics analysis to evaluate metabolic changes post-SPC25 knockdown.
- High-throughput molecular docking to screen for small molecule inhibitors of SPC25.
- In vitro validation of drug efficacy and mechanistic studies involving epithelial-mesenchymal transition (EMT).
Main Results:
- High SPC25 expression is significantly associated with adverse clinical outcomes in RCC.
- Suppression of SPC25 markedly reduces RCC cell proliferation, migration, and metabolic activity, inducing a less invasive phenotype.
- Mefloquine was identified as a potent inhibitor of RCC metastasis, acting at non-cytotoxic concentrations.
- Mefloquine exerts anti-metastatic effects by directly binding to SPC25 and inhibiting EMT.
Conclusions:
- SPC25 serves as a potential early biomarker for predicting metastatic risk in renal cell carcinoma.
- Mefloquine represents a novel therapeutic strategy for inhibiting RCC metastasis via SPC25 targeting and EMT inhibition.
- These findings offer new avenues for improving the clinical management and prognosis of patients with advanced RCC.
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