Abstract 64P
Background
Acidosis has been found to have multiple effects on tumor cells and immune cells among the tumor microenvironment. Ferroptosis is a nonapoptotic and iron-dependent form of cell death characterized by the accumulation of lipid peroxidation involved in various cancers. However, recent ferroptosis research in the breast cancer (BC) acidic microenvironment context remains limited. Given the evidence indicating the potential anti-cancer efficacy of metformin, the exact mechanism related to acidic tumor microenvironment has not yet been fully elucidated.
Methods
The ZFAND5/SLC3A2 axis was verified by in silico and multiple biological experiments and the ubiquitination of SLC3A2 was detected by immunoprecipitation. The level of ferroptosis was detected by the total/lipid reactive oxygen species (ROS) and glutathione (GSH) levels in BC cells, and the morphological changes of mitochondria were determined by transmission electron microscope. The mechanism in vivo was demonstrated by the in situ implantation tumor model in nude mice. Relation of BC cells and macrophages was determined by co-culture, western blot, flow cytometry and immunofluorescence.
Results
Acidosis induced ferroptosis in the ZFAND5/SLC3A2 independent manner to suppress tumor growth. Mechanistically, we demonstrated that acidosis increased total/lipid ROS level, decreased GSH level and induced the morphological changes of mitochondria. Specifically, acidosis restrained the protein stability of SLC3A2 by promoting its ubiquitination process. Furthermore, acidosis combined with metformin or macrophages, could work in a synergistic manner to suppress the proliferation and enhance the ferroptosis of BC cells.
Conclusions
This study demonstrated that the combination of acidosis and metformin with macrophages to induce ferroptosis might be a novel mechanism underlying its anti-BC effect. Additionally, we validated that SLC3A2 was a new ZFAND5 mediated ubiquitination substrate and proposed that targeting the ZFAND5/SLC3A2 axis could be a novel therapeutic strategy for BC patients.
Editorial acknowledgement
Clinical trial identification
Legal entity responsible for the study
The author.
Funding
National Natural Science Foundation of China.
Disclosure
The author has declared no conflicts of interest.
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