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Platycodin D inhibits non-small cell lung cancer bone metastasis by inducing ferroptosis through miR-877-3P/PNMA5
Zejuan Xie1, Ziao Zhou1, Shanshan Wang1
1Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Background:
Non-small cell lung cancer (NSCLC) frequently metastasizes to the bone, posing a significant threat to patient survival and quality of life owing to associated complications. Despite advancements in comprehensive treatment modalities for bone metastases of NSCLC, outcomes remain inadequate, necessitating continued exploration of therapeutic strategies and their underlying molecular mechanisms. Recently, Platycodin D (PD) has garnered attention for its anti-tumor properties. However, their regulatory mechanisms have not yet been extensively evaluated.
Methods:
This study used human NSCLC cell lines A549 and PC-9 to assess PD effects. CCK-8 assays were used to measure proliferation, while transwell and wound-healing tests were used to evaluate migration/invasion. MiRNA expression was profiled, with roles explored via mimics/inhibitors. Bioinformatically predicted miRNA targets were validated using dual-luciferase reporter assays. In vivo, a nude mouse NSCLC bone metastasis model (intracardiac injection of luciferase-labeled cells) assessed PD efficacy. Western blotting and qRT-PCR analyzed ferroptosis and epithelial-mesenchymal transition (EMT)-related expression.
Results:
Hsa-miR-877-3p was upregulated by PD treatment, and functional experiments demonstrated that the miR-877-3p-mimic enhanced PD's suppressive effects on NSCLC cell proliferation, colony formation, migration, and invasion, while the miR-877-3p-inhibitor abrogated these effects. Notably, dual-luciferase assays confirmed that hsa-miR-877-3p directly targeted PNMA Family Member 5 (PNMA5). This regulation influences ferroptosis pathways and potentially triggers EMT.
Conclusion:
Our findings suggest that the PD/miR-877-3p/PNMA5 axis represents a promising therapeutic target for bone metastasis in NSCLC. With further research and technological advancements, PD holds potential as an effective treatment strategy for bone metastasis in lung cancer.
Insights
Platycodin D (PD) inhibits non-small cell lung cancer (NSCLC) bone metastasis by upregulating miR-877-3p, which targets PNMA5. This pathway offers a potential therapeutic strategy for NSCLC bone metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) frequently metastasizes to bone, leading to poor prognosis.
- Current treatments for NSCLC bone metastases have limitations, necessitating novel therapeutic approaches.
- Platycodin D (PD) shows anti-tumor potential, but its regulatory mechanisms in NSCLC bone metastasis are unclear.
Purpose of the Study:
- To investigate the anti-metastatic effects of Platycodin D (PD) on non-small cell lung cancer (NSCLC) bone metastasis.
- To elucidate the molecular mechanisms underlying PD's action, focusing on miRNA regulation.
- To identify potential therapeutic targets for NSCLC bone metastasis.
Main Methods:
- Utilized human NSCLC cell lines (A549, PC-9) and a mouse bone metastasis model.
- Assessed PD effects on proliferation, migration, and invasion using CCK-8, transwell, and wound-healing assays.
- Analyzed miRNA expression, validated targets using dual-luciferase assays, and examined ferroptosis and EMT markers via Western blotting and qRT-PCR.
Main Results:
- PD treatment upregulated hsa-miR-877-3p expression in NSCLC cells.
- Hsa-miR-877-3p mimic enhanced PD's inhibitory effects, while an inhibitor abrogated them.
- Hsa-miR-877-3p directly targets PNMA5, influencing ferroptosis and epithelial-mesenchymal transition (EMT).
Conclusions:
- The PD/miR-877-3p/PNMA5 axis is a potential therapeutic target for NSCLC bone metastasis.
- PD demonstrates efficacy in suppressing NSCLC bone metastasis in preclinical models.
- Further research may establish PD as a viable treatment for lung cancer bone metastasis.
