Granzyme B triggers a prolonged pressure to die in Bcl-2 overexpressing cells, defining a window of opportunity for effective treatment with ABT-737

Sutton, V. R., Sedelies, K., Dewson, G., Christensen, M. E., Bird, P. I., Johnstone, R. W., Kluck, R. M., Trapani, J. A. and Waterhouse, N. J. (2012) Granzyme B triggers a prolonged pressure to die in Bcl-2 overexpressing cells, defining a window of opportunity for effective treatment with ABT-737. Cell Death and Disease, 3 7 Article No. e344: e344-1-e344-9. doi:10.1038/cddis.2012.73

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Author Sutton, V. R.
Sedelies, K.
Dewson, G.
Christensen, M. E.
Bird, P. I.
Johnstone, R. W.
Kluck, R. M.
Trapani, J. A.
Waterhouse, N. J.
Title Granzyme B triggers a prolonged pressure to die in Bcl-2 overexpressing cells, defining a window of opportunity for effective treatment with ABT-737
Journal name Cell Death and Disease   Check publisher's open access policy
ISSN 2041-4889
Publication date 2012-07
Sub-type Article (original research)
DOI 10.1038/cddis.2012.73
Open Access Status DOI
Volume 3
Issue 7 Article No. e344
Start page e344-1
End page e344-9
Total pages 9
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2013
Language eng
Formatted abstract
Overexpression of Bcl-2 contributes to resistance of cancer cells to human cytotoxic lymphocytes (CL) by blocking granzyme B (GraB)-induced mitochondrial outer membrane permeabilization (MOMP). Drugs that neutralise Bcl-2 (e.g., ABT-737) may therefore be effective adjuvants for immunotherapeutic strategies that use CL to kill cancer cells. Consistent with this we found that ABT-737 effectively restored MOMP in Bcl-2 overexpressing cells treated with GraB or natural killer cells. This effect was observed even if ABT-737 was added up to 16 h after GraB, after which the cells reset their resistant phenotype. Sensitivity to ABT-737 required initial cleavage of Bid by GraB (gctBid) but did not require ongoing GraB activity once Bid had been cleaved. This gctBid remained detectable in cells that were sensitive to ABT-737, but Bax and Bak were only activated if ABT-737 was added to the cells. These studies demonstrate that GraB generates a prolonged pro-apoptotic signal that must remain active for ABT-737 to be effective. The duration of this signal is determined by the longevity of gctBid but not activation of Bax or Bak. This defines a therapeutic window in which ABT-737 and CL synergise to cause maximum death of cancer cells that are resistant to either treatment alone, which will be essential in defining optimum treatment regimens
Keyword Granzyme
Lymphocyte
Apoptosis
Mitochondria
Cytochrome C Release
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Medicine Publications
 
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