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Regulation of apoptosis/necrosis execution in cadmium-treated human promonocytic cells under different forms of oxidative stress

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Abstract

Pulse-treatment of U-937 human promonocytic cells with cadmium chloride followed by recovery caused caspase-9/caspase-3-dependent, caspase-8-independent apoptosis. However, pre-incubation with the glutathione (GSH)-suppressing agent DL-buthionine-(S,R)-sulfoximine (cadmium/BSO), or co-treatment with H2O2 (cadmium/H2O2), switched the mode of death to caspase-independent necrosis. The switch from apoptosis to necrosis did not involve gross alterations in Apaf-1 and pro-caspase-9 expression, nor inhibition of cytochrome c release from mitochondria. However, cadmium/H2O2-induced necrosis involved ATP depletion and was prevented by 3-aminobenzamide, while cadmium/BSO-induced necrosis was ATP independent. Pre-incubation with BSO increased the intracellular cadmium accumulation, while co-treatment with H2O2 did not. Both treatments caused intracellular peroxide over-accumulation and disruption of mitochondrial transmembrane potential (ΔΨm). However, while post-treatment with N-acetyl-L-cysteine or butylated hydroxyanisole reduced the cadmium/BSO-mediated necrosis and ΔΨm disruption, it did not reduce the effects of cadmium/H2O2. Bcl-2 over-expression, which reduced peroxide accumulation without affecting the intracellular GSH content, attenuated necrosis generation by cadmium/H2O2 but not by cadmium/BSO. By contrast, AIF suppression, which reduced peroxide accumulation and increased the GSH content, attenuated the toxicity of both treatments. These results unravel the existence of two different oxidation-mediated necrotic pathways in cadmium-treated cells, one of them resulting from ATP-dependent apoptosis blockade, and the other involving the concurrence of multiple regulatory factors.

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Authors and Affiliations

  1. Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain

    P. Sancho, C. Fernández, D. Amrán, A. M. Ramos, E. de Blas & P. Aller

  2. Apoptose et Système Immunitaire, CNRS-URA 1961, Institut Pasteur, Paris, France

    P. Sancho, V. J. Yuste & S. A. Susin

  3. Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain

    P. Aller

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  1. P. Sancho
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  2. C. Fernández
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  3. V. J. Yuste
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  4. D. Amrán
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Sancho, P., Fernández, C., Yuste, V.J. et al. Regulation of apoptosis/necrosis execution in cadmium-treated human promonocytic cells under different forms of oxidative stress. Apoptosis 11, 673–686 (2006). https://doi.org/10.1007/s10495-006-5879-3

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  • DOI: https://doi.org/10.1007/s10495-006-5879-3

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