Abstract
Treatment with 0.2 mM hydrogen peroxide (H2O2) or with 0.5 mM cisplatin caused caspase-9 and caspase-3 activation and death by apoptosis in U-937 human promonocytic cells. However, treatment with 2 mM H2O2, or incubation with the glutathione suppressor DL-buthionine-(S,R)-sulfoximine (BSO) prior to treatment with cisplatin, suppressed caspase activation and changed the mode of death to necrosis. Treatment with 2 mM H2O2 caused a great decrease in the intracellular ATP level, which was partially prevented by 3-aminobenzamide (3-ABA). Correspondingly, 3-ABA restored the activation of caspases and the execution of apoptosis. By contrast, BSO plus cisplatin did not decrease the ATP levels, and the generation of necrosis by this treatment was not affected by 3-ABA. On the other hand, while all apoptosis-inducing treatments and treatment with 2 mM H2O2 caused Bax translocation from the cytosol to mitochondria as well as cytochrome c release from mitochondria to the cytosol, treatment with BSO plus cisplatin did not. Treatment with cisplatin alone caused Bid cleavage, while BSO plus cisplatin as well as 0.2 and 2 mM H2O2 did not. Bcl-2 overexpression reduced the generation of necrosis by H2O2, but not by BSO plus cisplatin. These results indicate the existence of different apoptosis/necrosis regulatory mechanisms in promonocytic cells subjected to different forms of oxidative stress.
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Abbreviations
- 3-ABA:
-
3-aminobenzamide
- BSO:
-
DL-buthionine-(S,R)-sulfoximine
- cisplatin, CDDP:
-
cis-platinum(II)-diammine dichloride
- FCS:
-
fetal calf serum
- GSH:
-
reduced glutathione
- H2O2:
-
hydrogen peroxide
- mAb:
-
monoclonal antibody
- pAb:
-
polyclonal antibody
- PARP:
-
poly (ADP-ribose) polymerase
- PBS:
-
phosphate-buffered saline
- PCD:
-
programmed cell death
- PI:
-
propidium iodide
- PKC:
-
protein kinase C
- ROS:
-
reactive oxygen species
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Acknowledgements
This work was supported in part by Grant SAF-2001-1219 from the Plan Nacional de Investigacion CientÃfica, Desarrollo e Investigación Tecnológica, Ministerio de Ciencia y TecnologÃa; by Grant 01/0946 from the Fondo de Investigación Sanitaria, Ministerio de Sanidad y Consumo; and by Grant 08.3/0011.3/2001 from the Comunidad Autónoma de Madrid, Spain, to PA; by the Associazione Italiana per la Ricerca sul Cancro (AIRC, Italy) to PB; and by the Program of Cooperation between the CSIC (Spain) and the CNR (Italy). AT and CF are recipients of predoctoral fellowships from the Ministerio de Ciencia y TecnologÃa, and PS of a predoctoral fellowship from the Ministerio de Educación, Cultura y Deporte, Spain. We thank Professors J Bréard and R Bisson for providing Bcl-2-transfected U-937 cells and anti-bc1 complex antibody, respectively.
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Troyano, A., Sancho, P., Fernández, C. et al. The selection between apoptosis and necrosis is differentially regulated in hydrogen peroxide-treated and glutathione-depleted human promonocytic cells. Cell Death Differ 10, 889–898 (2003). https://doi.org/10.1038/sj.cdd.4401249
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DOI: https://doi.org/10.1038/sj.cdd.4401249
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