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Momordins inhibit both AP-1 function and cell proliferation
Abstract:
The activation of Jun/Fos is a crucial factor in transmitting the tumor promoting signal from the extracellular environment to nuclear transcription machinery. One of the final steps in signal transduction is the binding of Jun/Fos to the AP-1 site in order to express gene transcription. Utilizing this concept, we screened about 100 extracts of natural plants to search for a Jun-Fos function inhibitor. The methanol extract of Ampelopsis radix reduced Jun/Foc retardation remarkably. The active principles of the extract were isolated and purified by repeated column chromatography and their structures were identified as oleanolic acid glycosides known as momordin I, Id, and Ie. These compounds reduced the Jun/Fos-DNA interaction and their activities were quantitated with liquid scintillation counting of corresponding bands. Among them, momordin I had the strongest inhibitory activity, with an IC50 value of 22.8 micrograms/ml. The methanol extract and momordin I, Id and Ie also showed cell cytotoxicity against human cancer cell lines. As expected from a gel shift assay, momordin I showed the strongest cytotoxicity and its IC50 value was from 7.280 micrograms/ml to 16.05 micrograms/ml depending on the cell line. With these data, it may be concluded that the mechanism of anticancer activity of momordin I comes from its inhibitory effect on the protein-DNA interaction. The in vivo test was done only with the methanol extract. The extract showed measurable anticancer activity against murine colon cancer. The wet tumor weight reduction rate was 17.73% at 90 mg/kg dose. We suggest that the Jun/Fos-DNA interaction results in cell cytotoxicity.
Insights
Natural plant extracts were screened for inhibitors of Jun/Fos protein-DNA interaction, a key in tumor promotion. Momordin I from Ampelopsis radix showed potent anticancer activity by blocking this interaction.
Area of Science:
- Molecular Biology
- Pharmacology
- Natural Product Chemistry
Background:
- Jun/Fos activation transmits tumor-promoting signals to nuclear transcription.
- Jun/Fos binding to the AP-1 site is essential for gene transcription and cancer progression.
Purpose of the Study:
- To identify natural plant extracts that inhibit Jun/Fos function.
- To investigate the anticancer potential of identified compounds.
Main Methods:
- Screening of approximately 100 plant extracts for Jun/Fos inhibitors.
- Isolation and structural identification of active compounds using chromatography.
- Quantification of Jun/Fos-DNA interaction inhibition via liquid scintillation counting.
- Assessment of cell cytotoxicity against human cancer cell lines.
- In vivo testing of the methanol extract against murine colon cancer.
Main Results:
- The methanol extract of Ampelopsis radix significantly reduced Jun/Fos-DNA interaction.
- Oleanolic acid glycosides, momordin I, Id, and Ie, were identified as active principles.
- Momordin I exhibited the strongest inhibitory activity (IC50: 22.8 µg/ml) and cytotoxicity (IC50: 7.28–16.05 µg/ml).
- The methanol extract demonstrated anticancer activity in vivo, reducing tumor weight by 17.73%.
Conclusions:
- Momordin I's anticancer activity is likely mediated by its inhibition of protein-DNA interaction.
- Ampelopsis radix and its constituents represent potential therapeutic agents for cancer treatment.