Reuterin promotes pyroptosis in hepatocellular cancer cells through mtDNA-mediated STING activation and caspase 8 expression
Hepatocellular carcinoma (HCC) is the most common form of liver cancer with poor prognosis. The available drugs for advanced HCC are limited and substantial therapeutic advances including new drugs and new combination therapies are still in urgent need. In this study, we found that the major metabolite of Lactobacillus reuteri (L. reuteri), reuterin showed great anti-HCC potential and could help in sorafenib treatment. Reuterin treatment impaired mitophagy and caused the aberrant clustering of mitochondrial nucleoids to block mitochondrial DNA (mtDNA) replication and mitochondrial fission, which could promote mtDNA leakage and subsequent STING activation in HCC cells. STING could activate pyroptosis and necroptosis, while reuterin treatment also induced caspase 8 expression to inhibit necroptosis through cleaving RIPK3 in HCC cells. Thus, pyroptosis was the main death form in reuterin-treated HCC cells and STING suppression remarkably rescued the growth inhibitory effect of reuterin and concurrently knockdown caspase 8 synergized to restrain the induction of pyroptosis. In conclusion, our study explains the detailed molecular mechanisms of the antitumor effect of reuterin and reveals its potential to perform as a combinational drug for HCC treatment.
Authors
- Youquan Bu (ORCID: https://orcid.org/0000-0002-0833-0640)
- Yunlong Lei (ORCID: https://orcid.org/0000-0002-7918-0221)
- Chuntao Tao (ORCID: https://orcid.org/0000-0001-8081-5661)
- Jun Zeng
- Xinyan Wan
- Xiao Xu (ORCID: https://orcid.org/0000-0002-3823-0122)
- Sen Wang (ORCID: https://orcid.org/0000-0001-6358-1672)
- Junhui Zhang (ORCID: https://orcid.org/0000-0001-5452-5994)
- Qian Chen (ORCID: https://orcid.org/0000-0002-3585-305X)
- Ying Zhang (ORCID: https://orcid.org/0000-0002-5939-0440)
- Lin Cui (ORCID: https://orcid.org/0000-0002-1152-3566)
- Chundong Zhang (ORCID: https://orcid.org/0000-0002-9760-7188)
- Zheng Du
- Hui Fan (ORCID: https://orcid.org/0009-0004-9954-8531)
- Longhao Li
- Jian Zhang (ORCID: https://orcid.org/0000-0001-9129-9092)
Institutions
- Chongqing Normal University (CN)
- The Affiliated Yongchuan Hospital of Chongqing Medical University (CN)
- Henan Provincial People's Hospital (CN)
- Chongqing Cancer Hospital (CN)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Cancer Letters
- Published
- 2024-08-15
- DOI
- https://doi.org/10.1016/j.canlet.2024.217183
- Citations
- 10
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 2.40
Funders
- Chongqing Postdoctoral Science Foundation
- National Natural Science Foundation of China
- Chongqing Medical University
- Institute for Advanced Studies in Basic Sciences
- Youth and Middle-aged Scientific and Technological Innovation Leading Talents Program of the Corps
- National Natural Science Foundation of China-Yunnan Joint Fund
- Chongqing Basic Science and Advanced Technology Research Program