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Urolithin C Exerts Anti-Endometrial Cancer Effects by Inducing Autophagy Through Specific Stimulation of ATF3
Ruiqi Hu1,2, Cuilan Liu2, Xiangyu Dong3
1Department of Gynecology, Binzhou Medical University Hospital, Binzhou, People's Republic of China.
Abstract:
Urolithin C (UC), a natural compound derived from the metabolism of ellagitannins by gut microbiota, exhibits diverse pharmacological and biological activities. However, its therapeutic potential and underlying mechanisms in endometrial cancer (EC) remain unclear. Functional assays were used to determine the effects of UC on the viability, proliferation, cell cycle, apoptosis, migration, and autophagy in EC cells. RNA sequencing was used to investigate the effect of UC on total gene expression in EC cells. The expression level of activating transcription factor 3 (ATF3) was evaluated using western blotting, real-time PCR, and immunofluorescence staining. Organoids and a mouse model of EC were used to analyze the anti-tumor effects of UC. UC significantly inhibited the malignant behavior of EC cells. High-throughput transcriptome sequencing revealed a close association between autophagy and UC treatment, and identified ATF3 as a key downstream factor. UC treatment increased the expression of ATF3, which was primarily localized to the nucleus. Elevated ATF3 levels positively correlated with the survival of patients with EC. ATF3 knockdown rescued the effects of UC on cell viability, migration, and autophagy. Furthermore, EC organoid and in vivo experiments showed that UC markedly reduced organoid viability and EC tumor growth. UC exerts anti-EC activity by promoting ATF3 expression, thereby inhibiting the malignant behavior of EC cells and promoting autophagic cell death.
Insights
Urolithin C (UC) inhibits endometrial cancer (EC) by increasing activating transcription factor 3 (ATF3) expression, promoting cell death and reducing tumor growth. This natural compound shows promise for EC treatment.
Area of Science:
- Natural Products Chemistry
- Cancer Biology
- Molecular Pharmacology
Background:
- Endometrial cancer (EC) remains a significant health concern with unmet therapeutic needs.
- Urolithin C (UC), a gut microbiota metabolite of ellagitannins, possesses known bioactivities but its role in EC is unexplored.
Purpose of the Study:
- To investigate the therapeutic potential and molecular mechanisms of Urolithin C (UC) in endometrial cancer (EC).
- To evaluate UC's effects on EC cell behavior, gene expression, and tumor growth.
Main Methods:
- In vitro functional assays (viability, proliferation, cell cycle, apoptosis, migration, autophagy) on EC cells.
- RNA sequencing for global gene expression analysis.
- Western blotting, real-time PCR, immunofluorescence for ATF3 validation.
- EC organoid and in vivo mouse models for anti-tumor efficacy.
Main Results:
- UC significantly inhibited EC cell viability, proliferation, migration, and induced apoptosis and autophagy.
- RNA sequencing identified autophagy as a key pathway affected by UC, highlighting ATF3 as a crucial downstream mediator.
- UC treatment upregulated nuclear ATF3 expression, which correlated with improved patient survival.
- ATF3 knockdown reversed UC's inhibitory effects on EC cells.
- UC reduced EC organoid viability and tumor growth in vivo.
Conclusions:
- Urolithin C (UC) demonstrates significant anti-cancer activity against endometrial cancer (EC).
- UC exerts its effects by upregulating activating transcription factor 3 (ATF3), which inhibits malignant cell behavior and promotes autophagic cell death.
- UC represents a potential therapeutic agent for endometrial cancer, warranting further clinical investigation.
