2. Academic Validation
  3. Urolithin A exerts anti-tumor effects on gastric cancer via activating autophagy-Hippo axis and modulating the gut microbiota

Urolithin A exerts anti-tumor effects on gastric cancer via activating autophagy-Hippo axis and modulating the gut microbiota

  • Naunyn Schmiedebergs Arch Pharmacol. 2024 Mar 15. doi: 10.1007/s00210-024-03043-5.
Yixiao Qiao # 1 2 3,  Qiaoyun Xia # 2,  Xukun Cao # 4,  Jingyuan Xu 5,  Zhengdong Qiao 3,  Longyun Wu 2,  Zhirong Chen 6,  Longbao Yang 7,  Xiaolan Lu 8
Affiliations

Affiliations

  • 1 Department of Gastroenterology, the Affiliated Suzhou Hospital of Nanjing Medical University, 16 Baita West Road, Suzhou, 215001, China.
  • 2 Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China.
  • 3 Center for Medical Research and Innovation, Shanghai Pudong Hospital of Fudan University, Shanghai, 201399, China.
  • 4 Department of General Intensive Care Unit, Henan Provincial Chest Hospital, Zhengzhou, 450003, China.
  • 5 Department of Gastroenterology, the Affiliated Suzhou Hospital of Nanjing Medical University, 16 Baita West Road, Suzhou, 215001, China. 498520087@qq.com.
  • 6 Department of Gastroenterology, the Affiliated Suzhou Hospital of Nanjing Medical University, 16 Baita West Road, Suzhou, 215001, China. czr88188@163.com.
  • 7 Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China. 350929483@qq.com.
  • 8 Department of Gastroenterology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China. xiaolan_lu@163.com.
  • # Contributed equally.
PMID: 38489081 DOI: 10.1007/s00210-024-03043-5
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.

Keywords

Autophagy; Gastric cancer; Gut microbiota; Hippo pathway; Urolithin A; Warburg effect.

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