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MCF7 cells were cultured in pH6.6 medium for 6/12/24h

ABSTRACT: 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 researches in the breast cancer (BC) acidic microenvironment context remains unrevealed. Acidosis induced ferroptosis in the ZFAND5/SLC3A2 independent manner to suppress tumor growth using in silico and multiple biological experiments. 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. This study firstly demonstrated that the ability of combination of acidosis and metformin, macrophages to induce ferroptosis might be a novel mechanism underlying its anti-BC effect.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239732 | GEO | 2025/11/01

REPOSITORIES: GEO

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Project description:Ferroptosis is a form of regulated cell death characterized by iron-dependent overaccumulation of lipid peroxides. It can be prevented by cellular mechanisms such as GPX4-mediated elimination of the lipid peroxides at the cost of glutathione (GSH). Since originally being discovered as a property of RAS-mutant cancer cells, ferroptosis has been shown to be regulated by several important oncogenes and tumor suppressors. In particular, LIFR, the receptor of the pleiotropic cytokine LIF, has recently been shown to be required for ferroptosis, as loss of Lifr in mouse liver tumor confers the cells resistance to ferroptosis. In this study, however, we found that the LIFR-targeting drugs, EC330 and EC359, are potent inducers of ferroptosis, thus reflecting an interesting “gain-of-function” effect of EC330/EC359 on LIFR-associated ferroptosis. Treatment of various types of cells with EC330/EC359 causes a rapid nonapoptotic cell death with characteristic morphology of ferroptosis, which can be inhibited by iron chelator (DFO) and lipid ROS scavenger (Fer-1), but not pan-caspase inhibitor (z-VAD-fmk). Consistent with previous observations, the efficiency of EC330/EC359 appears to be correlated with the expression levels of LIF and LIFR. RNA-seq analysis showed that the EC330/EC359 treatment leads to (i) a gene expression profile highly resembling that of RSL3, the GPX4-targeting ferroptosis inducer, and (ii) a specific decrease of expression of a few gene encoding membrane-located proteins, especially those located on the mitochondria (e.g., TOMM6 and COX14), implying defects in cellular/mitochondrial membrane functions. Indeed, transmission electron microscopy imaging of the EC330/EC359-treated cells shows shrunken mitochondria and loss of mitochondrial cristae. EC330/EC359 also decreases the activity of GPX4 in the cells to the level comparable with RSL3; meanwhile, the intracellular level of GSH is also decreased, and thus GPX4 inactivation and GSH depletion may jointly disable the cells to eliminate the toxic lipid peroxides. Lastly, although the STAT3 and AKT signaling pathways downstream of LIFR are inhibited by EC330/EC359, inhibition of these pathways per se can only induce non-ferroptotic cell death, suggesting that the EC330/EC359-induced ferroptosis is independent of these downstream pathways; the LIFR-NFkB-LCN2 axis discovered recently in mouse liver tumor cells might not explain the EC330/EC359-induced ferroptosis either, because LCN2 is not detectable in the herein used cell lines. Taken together, these results reveal an unexpected role of the LIFR-targeting drugs EC330/EC359 as potent inducer of ferroptosis and, in combination with previous studies, suggest that there could be either unknown mechanism for the LIFR-associated ferroptosis or unknown target for EC330/EC359 to effect the ferroptosis induction.

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MCF7 cells were cultured in pH6.6 medium for 6/12/24h

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