Abstract
Gastric cancer (GC) treatment regimens are still unsatisfactory. Recently, Urolithin A (UroA) has gained tremendous momentum due to its anti-tumor properties. However, the therapeutic effect and underlying mechanisms of UroA in GC are unclear. We explored the effects and related mechanisms of UroA on GC both in vivo and in vitro. A Cell Counting Kit-8 was used to determine the influence of UroA on the proliferation of GC cell lines. The Autophagy inhibitor 3‐methyladenine (3MA) was employed to clarify the role of autophagy in the anti-tumor effect of UroA. Simultaneously, we detected the core-component proteins involved in autophagy and its downstream pathways. Subsequently, the in vivo anti-tumor effect of UroA was determined using a xenograft mouse model. Western blotting was used to detect the core protein components of the anti-tumor pathways, and 16S rDNA sequencing was used to detect the effect of UroA on the gut microbiota. We found that UroA suppressed tumor progression. The use of 3MA undermined the majority of the inhibitory effect of UroA on tumor cell proliferation, further confirming the importance of autophagy in the anti-tumor effect of UroA. Invigorating of autophagy activated the downstream Hippo pathway, thereby inhibiting the Warburg effect and promoting cell apoptosis. In addition, UroA modulated the composition of the gut microbiota, as indicated by the increase of probiotics and the decrease of pathogenic bacteria. Our research revealed new anti-tumor mechanisms of UroA, which may be a promising candidate for GC treatment.
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The 16S rDNA seq data was has been deposited into the NCBI Sequence Read Archive database (PRJNA1076693).
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Funding
This work is supported by the National Natural Science Foundation of China (82070587), the Pudong New Area Clinical Characteristic Discipline Project (Grant No. PWYts2021-11), the Affiliated Suzhou Hospital of Nanjing Medical University (Szslyyrc2023022), and the Key Discipline of Shanghai Pudong Hospital (Zdxk2020-07).
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Jingyuan Xu, Qiaoyun Xia, Zhirong Chen and Xiaolan Lu conceived and designed the study. Yixiao Qiao, Qiaoyun Xia, Xukun Cao, Jingyuan Xu, Zhengdong Qiao, Longyun Wu, Zhirong Chen, Longbao Yang and Xiaolan Lu conducted the experiment. Jingyuan Xu, and Qiaoyun Xia analyzed the data. Qiaoyun Xia wrote the manuscript. Jingyuan Xu, Zhirong Chen, Longbao Yang and Xiaolan Lu revised the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.
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All procedures performed in studies involving animal experiments were in accordance with the ethical standards of the Animal Ethics Committee of Fudan University Pudong Medical Center. and with the National Institutes of Health Guide for the care and use of Laboratory animals (NIH Publications No. 8023, revised 1978).
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Qiao, Y., Xia, Q., Cao, X. et al. Urolithin A exerts anti-tumor effects on gastric cancer via activating autophagy-Hippo axis and modulating the gut microbiota. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03043-5
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DOI: https://doi.org/10.1007/s00210-024-03043-5