Document Detail


Bcl-2 inhibits apoptosis by increasing the time-to-death and intrinsic cell-to-cell variations in the mitochondrial pathway of cell death.
MedLine Citation:
PMID:  20563668     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BH3 mimetics have been proposed as new anticancer therapeutics. They target anti-apoptotic Bcl-2 proteins, up-regulation of which has been implicated in the resistance of many cancer cells, particularly leukemia and lymphoma cells, to apoptosis. Using probabilistic computational modeling of the mitochondrial pathway of apoptosis, verified by single-cell experimental observations, we develop a model of Bcl-2 inhibition of apoptosis. Our results clarify how Bcl-2 imparts its anti-apoptotic role by increasing the time-to-death and cell-to-cell variability. We also show that although the commitment to death is highly impacted by differences in protein levels at the time of stimulation, inherent stochastic fluctuations in apoptotic signaling are sufficient to induce cell-to-cell variability and to allow single cells to escape death. This study suggests that intrinsic cell-to-cell stochastic variability in apoptotic signaling is sufficient to cause fractional killing of cancer cells after exposure to BH3 mimetics. This is an unanticipated facet of cancer chemoresistance.
Authors:
Joanna Skommer; Tom Brittain; Subhadip Raychaudhuri
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Apoptosis : an international journal on programmed cell death     Volume:  15     ISSN:  1573-675X     ISO Abbreviation:  Apoptosis     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-01     Completed Date:  2010-12-30     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  9712129     Medline TA:  Apoptosis     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1223-33     Citation Subset:  IM    
Affiliation:
School of Biological Sciences, University of Auckland, Thomas Bld., 3a Symonds Street, Auckland, 1142, New Zealand. J.Skommer@auckland.ac.nz
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MeSH Terms
Descriptor/Qualifier:
Apoptosis*
Apoptosis Regulatory Proteins / metabolism
BH3 Interacting Domain Death Agonist Protein / metabolism*
Benzopyrans / metabolism,  pharmacology
Cell Line, Tumor
Cytochromes c / metabolism
Flow Cytometry
Genes, bcl-2
Humans
Jurkat Cells
Mitochondria / metabolism*
Nitriles / metabolism,  pharmacology
Proto-Oncogene Proteins c-bcl-2 / metabolism*
Signal Transduction
Up-Regulation
bcl-2-Associated X Protein / metabolism
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/BH3 Interacting Domain Death Agonist Protein; 0/Benzopyrans; 0/Nitriles; 0/Proto-Oncogene Proteins c-bcl-2; 0/bcl-2-Associated X Protein; 0/ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; 9007-43-6/Cytochromes c
Comments/Corrections

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