Ferroptosis is considered a distinctive form of cell death compared to other types of death such as apoptosis. It is known to result from iron-dependent accumulation of lipid peroxides rather than caspase activation. However, we reported recently that ferroptosis interplays with apoptosis. In this study, we investigated a possible mechanism of this interplay between ferroptosis and apoptosis. Results from our studies reveal that combined treatment of the ferroptotic agent erastin and the apoptotic agent TRAIL effectively disrupted mitochondrial membrane potential (ΔΨm) and subsequently promoted caspase activation. The alterations of mitochondrial membrane potential are probably due to an increase in oligomerization of BAX and its accumulation at the mitochondria during treatment with erastin and TRAIL. Interestingly, the combined treatment-promoted apoptosis was effectively inhibited in BAX-deficient HCT116 cells, but not BAK-deficient cells. These results indicate that the BAX-associated mitochondria-dependent pathway plays a pivotal role in erastin-enhanced TRAIL-induced apoptosis.
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Activating transcription factor 4
Bcl-2 homologous antagonist killer
Bcl-2–associated X protein
B cell lymphoma 2
B-cell lymphoma-extra large
BH3 interacting-domain death agonist
CCAAT-enhancer-binding protein homologous protein
Death-inducing signaling complex
Death receptor 4
Death receptor 5
Ethylene glycol-bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
Eukaryotic initiation factor 2α
Green fluorescent protein
Poly [ADP-ribose] polymerase 1
Protein kinase RNA-like endoplasmic reticulum kinase
p53 upregulated modulator of apoptosis
Tumor necrosis factor-related apoptosis-inducing ligand
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We thank Christine Burr (Department of Surgery, University of Pittsburgh) for her critical review of the manuscript.
Grant sponsor: NCI R03CA205267, R03CA212125, and P30CA047904
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The authors declare no competing financial interests.
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Lee, YS., Kalimuthu, K., Park, Y.S. et al. BAX-dependent mitochondrial pathway mediates the crosstalk between ferroptosis and apoptosis. Apoptosis 25, 625–631 (2020). https://doi.org/10.1007/s10495-020-01627-z
- Mitochondria-dependent pathway