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.
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Data availability
The raw sequence and processed data were deposited in the NCBI’s Sequence Read Archive (SRA) with accession number PRJNA939824. The data presented in this study are available on request from the corresponding author.
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Acknowledgements
The authors are grateful to all staff at the Laboratory Animal Center of Zhujiang Hospital of Southern Medical University, and all staff at the Laboratory Center of Zhujiang Hospital of Southern Medical University. We thank Prof. Xun Sun and Dr. Wenjun Li for helpful discussions and insightful comments. We also thank Editage (www.editage.com) for English language editing.
Funding
This work was supported by the National Natural Science Foundation of China (Grant Number: 82072762 and 32001040); National Key Research and Development Program of China (Grant Number: 2021YFA0910700 and 2018YFA0902701), and Guangdong Science and Technology Department (Grant Number: 2020B1212030004); Guangdong Introducing Innovative and Entrepreneurial Teams (Grant Number: 2019BT02Y198) and Shenzhen Key Laboratory for Cancer Metastasis and Personalized Therapy (Grant Number: ZDSYS20210623091811035); Guangdong Basic and Applied Basic Research Foundation (Grant Number: 2023A1515030045) and Presidential Foundation of Zhujiang Hospital, Southern Medical University (Grant Number: yzjj2022ms4).
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Conceptualization: HS, YK and JDH; Methodology: TL; Software: JZ; Validation: JC; Formal analysis: JC; Investigation: NZ, YH; Resources: CM; Data curation: JZ; Writing—original draft preparation: JC; Writing—review and editing: MZ, JJ; Visualization: JC; Supervision: HS, YK, and JDH; Project administration: JC; Funding acquisition: HS, YK, and JDH. All authors read and approved the final manuscript.
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Chen, J., Li, T., Zhou, N. et al. Engineered Salmonella inhibits GPX4 expression and induces ferroptosis to suppress glioma growth in vitro and in vivo. J Neurooncol 163, 607–622 (2023). https://doi.org/10.1007/s11060-023-04369-5
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DOI: https://doi.org/10.1007/s11060-023-04369-5