Document Detail

Hypersensitivity of mtDNA-depleted cells to staurosporine-induced apoptosis: roles of Bcl-2 downregulation and cathepsin B.
MedLine Citation:
PMID:  21068357     Owner:  NLM     Status:  In-Data-Review    
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(0)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 pan-caspase inhibitor failed to completely prevent PARP-1 cleavage and DNA fragmentation in these cells, suggesting that caspase-independent mechanisms are responsible for cell death even if caspases are activated. Finally, we show that cathepsin B is released in the cytosol of ρ(0) cells in response to staurosporine, suggesting that the absence of mitochondrial activity leads to a facilitated permeabilization of lysosomal membranes in response to staurosporine.
Guillaume Rommelaere; Sébastien Michel; Ludovic Mercy; Antoine Fattaccioli; Catherine Demazy; Noelle Ninane; Andrée Houbion; Patricia Renard; Thierry Arnould
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Publication Detail:
Type:  Journal Article     Date:  2010-11-10
Journal Detail:
Title:  American journal of physiology. Cell physiology     Volume:  300     ISSN:  1522-1563     ISO Abbreviation:  Am. J. Physiol., Cell Physiol.     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-04-27     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901225     Medline TA:  Am J Physiol Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  C1090-106     Citation Subset:  IM    
Laboratory of Biochemistry and Cell Biology, Faculty of Sciences, Univ. of Namur (FUNDP 61 rue de Bruxelles, 5000 Namur, Belgium.
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