Journal article

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

VR Sutton, K Sedelies, G Dewson, ME Christensen, PI Bird, RW Johnstone, RM Kluck, JA Trapani, NJ Waterhouse



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 re..

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Awarded by NHMRC

Funding Acknowledgements

This work was supported by funding from the NHMRC (Project Grant and CDA Award to NJW, project grants #575559 and #637335 to RMK, Programme Grant to JAT, RJW and PB), the Australian Research Council (Futures fellowship to NJW), project grants from the Leukaemia Foundation Queensland and the Prostate Cancer Foundation Australia to NJW. We thank Abbot Laboratories for ABT-737, Ms Kate Whitecross, Dr. Jamie Lopez and Dr. Daniella Brasacchio for helpful technical discussions, Ms Diana Motion for editorial assistance, and Mr Kevin Thia for graphical expertise. Owing to editorial limits we were unable to cite all relevant publications.