Résumé
We show that mitochondrial DNA (mtDNA)-depleted 143B cells are hypersensitive to staurosporine- induced cell death as evidenced by a more pronounced DNA fragmentation, a stronger activation of caspase-3, an enhanced poly- (ADP-ribose) polymerase-1 (PARP-1) cleavage, and a more dramatic cytosolic release of cytochrome c. We also show that B-cell CLL/ lymphoma-2 (Bcl-2), B-cell lymphoma extra large (Bcl-X L), and myeloid cell leukemia-1 (Mcl-1) are constitutively less abundant in mtDNA-depleted cells, that the inhibition of Bcl-2 and Bcl-X L can sensitize the parental cell line to staurosporine-induced apoptosis, and that overexpression of Bcl-2 or Bcl-X L can prevent the activation of caspase-3 in ρ°143B cells treated with staurosporine. Moreover, the inactivation of cathepsin B with CA074-Me significantly reduced cytochrome c release, caspase-3 activation, PARP-1 cleavage, and DNA fragmentation in mtDNA-depleted cells, whereas the pancaspase inhibitor failed to completely prevent PARP-1 cleavage and DNA fragmentation in these cells, suggesting that caspaseindependent mechanisms are responsible for cell death even if caspases are activated. Finally, we show that cathepsin B is released in the cytosol of ρ° cells in response to staurosporine, suggesting that the absence of mitochondrial activity leads to a facilitated permeabilization of lysosomal membranes in response to staurosporine. © 2011 the American Physiological Society.
langue originale | Anglais |
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Pages (de - à) | 1090-1106 |
Nombre de pages | 17 |
journal | American Journal of Physiology - Cell Physiology |
Volume | 300 |
Numéro de publication | 5 |
Les DOIs | |
Etat de la publication | Publié - mai 2011 |
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