BAX-dependent mitochondrial pathway mediates the crosstalk between ferroptosis and apoptosis
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SHORT COMMUNICATION
BAX‑dependent mitochondrial pathway mediates the crosstalk between ferroptosis and apoptosis Young‑Sun Lee1 · Kalishwaralal Kalimuthu1 · Yong Seok Park2 · Xu Luo3 · M. Haroon A. Choudry1 · David L. Bartlett1 · Yong J. Lee1
© Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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. Keywords Ferroptosis · Apoptosis · Crosstalk · BAX · Mitochondria-dependent pathway Abbreviations ATF4 Activating transcription factor 4 BAK Bcl-2 homologous antagonist killer BAX Bcl-2–associated X protein Bcl-2 B cell lymphoma 2 Bcl-xL B-cell lymphoma-extra large BH3 Bcl-2 homology BID BH3 interacting-domain death agonist C/EBP CCAAT-enhancer-binding proteins CHOP CCAAT-enhancer-binding protein homologous protein DAPI 40,6-Diamidino-2-phenylindole DISC Death-inducing signaling complex DR Death receptor DR4 Death receptor 4 * Yong J. Lee [email protected] 1
Department of Surgery, School of Medicine, University of Pittsburgh, 5117 Centre Ave, Pittsburgh, PA 15213, USA
2
Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA 15213, USA
3
Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
DR5 Death receptor 5 EGTA Ethylene glycol-bis(β-aminoethyl ether)N,N,N′,N′-tetraacetic acid eIF2α Eukaryotic initiation factor 2α ER Endoplasmic reticulum ERA Erastin GFP Green fluorescent protein HB Homogenization buffer HEPES 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid HRP Horseradish peroxidase JC-1 5,50,6,60-Tetrachloro-1,10,3,30-tetraethylbenzimidazol carbocyanineiodid PARP-1 Poly [ADP-ribose] polymerase 1 PERK Protein kinase RNA-like endoplasmic reticulum kinase PUMA p53 upregulated modulator of apoptosis SD Standard deviation TRAIL Tumor necrosis factor-related apoptosis-inducing ligand WT Wild-type
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Apoptosis
Introduction Ferroptos
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