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Published on: July 21, 2018
Formosanin C inhibits non-small-cell lung cancer progression by blocking MCT4/CD147-mediated lactate export
Jiaqi Li1, Zongjin Wu1, Geer Chen1
1Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Room I01-119, I building, Avenida Wai Long, Taipa, Macau, China.
Background:
Tumor cells reprogram their metabolic network to maintain their uncontrolled proliferation, metastasis, and resistance to cancer therapy. Treatments targeting abnormal cellular metabolism may have promising therapeutic effects. Formosanin C (FC), a diosgenin derived from the rhizoma of Paris polyphylla var. yunnanensis, has shown potent anti-cancer activities against various cancer types. However, the effect of FC on cancer metabolism remains to be elucidated.
Purpose:
In this research, we aimed to elucidate FC's effect and potential mechanisms on metabolism in lung cancer.
Methods:
Colony formation, transwell cell migration, and apoptosis were detected in multiple NSCLC cell lines to assess the cytotoxicity of FC. 1H NMR metabolomics approach was applied to screen the differential metabolites in H1299 cells and the culture medium. Western blotting, flow cytometry, and other molecular biological techniques were performed to verify the latent mechanism involved in metabolites. An allograft tumor model was employed to investigate the anti-tumor effects of FC in vivo.
Results:
FC significantly inhibited monoclonal formation and migration and induced cell cycle arrest and apoptosis in NSCLC cells. FC altered the abundances of 12 metabolites in lung cancer cells and 3 metabolites in the medium. These differential metabolites are primarily involved in glycolysis, citric acid cycle, and glutathione pathways. Notably, there was a remarkable increase in intracellular lactate and a reduction in extracellular lactate after FC treatment. Mechanically, FC downregulated the expression of MCT4 and CD147, blocking the export of lactate. Furthermore, FC also evoked mitochondrial dysfunction coupled with excessive oxidative stress, decreased mitochondrial membrane potential, ATP production reduction, glutathione depletion, and Ca2+ overload. Moreover, FC suppressed tumor progression in vivo with reduced protein levels of the MCT4 and CD147 in tumor tissues.
Conclusion:
FC inhibits lung cancer growth by the novel mechanism in which MCT4/CD147-mediated inhibition of lactate transport and disruption of mitochondrial functions are involved.
Insights
Formosanin C (FC) inhibits lung cancer growth by disrupting cancer cell metabolism. It blocks lactate export and impairs mitochondrial function, offering a novel therapeutic strategy for non-small cell lung cancer (NSCLC).
Area of Science:
- Biochemistry and Molecular Biology
- Cancer Metabolism Research
- Pharmacology
Background:
- Cancer cells exhibit altered metabolism to support uncontrolled proliferation and therapy resistance.
- Targeting cancer metabolism presents a promising therapeutic avenue.
- Formosanin C (FC), a natural compound, shows anti-cancer potential but its metabolic effects are unclear.
Purpose of the Study:
- To elucidate the effects of Formosanin C (FC) on lung cancer metabolism.
- To investigate the underlying mechanisms of FC's action in lung cancer.
Main Methods:
- Cytotoxicity assays (colony formation, migration, apoptosis) in NSCLC cell lines.
- 1H NMR metabolomics to identify metabolic changes in cells and medium.
- Western blotting, flow cytometry, and in vivo allograft tumor models to confirm mechanisms.
Main Results:
- FC inhibited NSCLC cell proliferation, migration, and induced apoptosis.
- FC altered key metabolites involved in glycolysis, citric acid cycle, and glutathione pathways.
- FC reduced lactate export by downregulating MCT4/CD147, induced mitochondrial dysfunction, oxidative stress, and Ca2+ overload.
Conclusions:
- FC inhibits lung cancer growth through a novel mechanism involving MCT4/CD147-mediated lactate transport inhibition.
- Disruption of mitochondrial function and induction of oxidative stress are key effects of FC.
- FC demonstrates significant anti-tumor effects in vivo, highlighting its therapeutic potential.
