BID- and BAX-mediated mitochondrial pathway dominates A-1331852-induced apoptosis in senescent A549 cells
Recovered senescent tumor cells harbor higher migration and invasion potential, owing to which they play a crucial role in tumor recurrence and drug resistance. The aim of this study was to explore the ability of BH3 mimetics in clearing senescent A549 cells and elucidate their underlying killing me...
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Veröffentlicht in: | Biochemical and biophysical research communications 2022-10, Vol.627, p.160-167 |
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Zusammenfassung: | Recovered senescent tumor cells harbor higher migration and invasion potential, owing to which they play a crucial role in tumor recurrence and drug resistance. The aim of this study was to explore the ability of BH3 mimetics in clearing senescent A549 cells and elucidate their underlying killing mechanism. Doxorubicin-induced cell senescence was determined using augmented senescence-associated beta-galactosidase (SA-β-Gal) staining and increased P16 expression. CCK-8 and crystal violet staining demonstrated that A-1331852, BH3 mimetic, could kill senescent tumor cells without affecting the proliferating cells. A-1331852 induced caspase-dependent senescent cell death accompanied by nuclear concentration, decreased mitochondrial membrane potential, and cleavage of poly (ADP-ribose) polymerase. Most importantly, A-1331852 upregulated the expression of BID and BAX indicating their role in mediating A-1331852-induced apoptosis in senescent A549 cells. The results of fluorescence resonance energy transfer showed that A-1331852 loosened or even released the binding between BCL-xL and tBID, releasing tBID. In addition, A-1331852 also dissociated the binding between BCL-xL and BAX, eventually leading to BAX oligomerization in the mitochondria, and resulting in apoptosis via the mitochondrial pathway. In conclusion, our data demonstrate for the first time that A-1331852 promotes apoptosis of senescent A549 cells by influencing the interaction between BCL-xL and tBID and that between BCL-xL and BAX.
•BID plays a key role in A-1331852 induced apoptosis of senescent A549 cells.•A-1331852 induces apoptosis of senescent A549 cells by the mitochondrial pathway.•BAX mediates A-1331852-induced apoptosis in senescent A549 cells. |
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ISSN: | 0006-291X 1090-2104 |
DOI: | 10.1016/j.bbrc.2022.08.023 |