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  3. Engineered Salmonella inhibits GPX4 expression and induces ferroptosis to suppress glioma growth in vitro and in vivo

Engineered Salmonella inhibits GPX4 expression and induces ferroptosis to suppress glioma growth in vitro and in vivo

  • J Neurooncol. 2023 Jun 23. doi: 10.1007/s11060-023-04369-5.
Jiawen Chen 1,  Ting Li 1 2,  Nan Zhou 3,  Yige He 4,  Jiasheng Zhong 1,  Chengcheng Ma 1,  Meiqin Zeng 1 2,  Jingsen Ji 1,  Jian-Dong Huang 4 5 6 7 2,  Yiquan Ke 8,  Haitao Sun 9 10
Affiliations

Affiliations

  • 1 Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
  • 2 Department of Laboratory Medicine, Clinical Biobank Center, Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.
  • 3 ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, 311215, China.
  • 4 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong Special Administrative Region, 999077, China.
  • 5 Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences (CAS), Chinese Academy of Sciences, Shenzhen, 518055, China.
  • 6 Clinical Oncology Center, Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518055, China.
  • 7 Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen University, Guangzhou, 510120, China.
  • 8 Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China. [email protected].
  • 9 Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China. [email protected].
  • 10 Department of Laboratory Medicine, Clinical Biobank Center, Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China. [email protected].
PMID: 37351767 DOI: 10.1007/s11060-023-04369-5
Abstract

Purpose: Glioma is a life-threatening malignancy where conventional therapies are ineffective. Bacterial cancer therapy has shown potential for glioma treatment, in particular, the facultative anaerobe Salmonella has been extensively studied. Meanwhile, Ferroptosis is a newly characterized form of cell death. Nevertheless, the role of Ferroptosis in Salmonella-induced tumour cell death remains unclear. Therefore, we aim to elucidate whether Salmonella YB1 exerts therapeutic effects via inducing Ferroptosis in glioma.

Methods: Following Salmonella YB1 Infection, mRNA sequencing was applied to detect ferroptosis-related gene expression and the levels of Reactive Oxygen Species, malondialdehyde, and glutathione were quantified. Transmission electron microscopy (TEM) was then used to observe the changes in the mitochondrial morphology of glioma cells. The role of Ferroptosis in the anti-tumor effect of YB1 was assessed in vivo in mouse tumor xenograft models.

Results: Whole-transcriptome analysis revealed that Salmonella YB1 Infection alters ferroptosis-related gene expression in the U87 glioma cell line. Moreover, we found that Salmonella-induced Ferroptosis is correlated with reduced levels of glutathione and glutathione peroxidase-4 (GPX4) and increased levels of Reactive Oxygen Species and malondialdehyde in vitro. Meanwhile, TEM revealed that mitochondria are shrunken and mitochondrial membrane density increases in infected glioma cells. Experiments in vivo further showed that tumor growth in the Salmonella-treated group was significantly slower compared to the control and Fer-1 groups. However, Salmonella-induced tumor suppression can be reversed in vivo by Fer-1 treatment.

Conclusion: Salmonella YB1 inhibits GPX4 expression and induces Ferroptosis to suppress glioma growth. Hence, Ferroptosis regulation might represent a promising strategy to improve the efficacy of Bacterial cancer therapy.

Keywords

Engineered Salmonella; Ferroptosis; GPX4; Glioma.

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