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Caspase independence of radio-induced cell death

Oncogene volume 25, pages 7758–7770 (2006)Cite this article

Abstract

Colon carcinoma cells subjected to γ-irradiation (4 Gy) manifest signs of apoptosis (caspase activation, chromatin condensation, phosphatidylserine (PS) exposure on the cell surface, sub-diploid DNA content), correlating with their radiosensitivity, which is increased in cells lacking the 14-3-3σ protein as compared to wild-type controls. Inhibition of caspases by addition of Z-Val-Ala-DL-Asp (OMe)-fluoromethylketone, by stable transfection with the Baculovirus gene coding for p35, or by Bax knockout reduced all signs of apoptosis, yet failed to suppress radio-induced micro- and multinucleation. Moreover, pharmacological caspase inhibition, p35 expression or Bax knockout had no effect on the clonogenic survival that was reduced by γ-irradiation and caspase inhibition failed to abolish the increased radiosensitivity of 14-3-3σ-deficient cells. Micro- and multinucleation was detectable among non-apoptotic cells lacking PS exposure, as well as among cells undergoing apoptosis. Moreover, a fraction of micro- or multinucleated cells manifested caspase activation, and videomicroscopic analyses revealed that such cells could succumb to caspase-dependent apoptosis. Altogether, these results suggest that genomic instability induced by γ-irradiation can trigger apoptosis, although apoptosis is dispensable for radio-induced clonogenic death.

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Abbreviations

Casp-3a:

activated caspase-3

FACS:

fluorescence-activated cell sorter

GFP:

green fluorescent protein

MN:

micronuclei

PI:

propidium iodide

PS:

phosphatidylserine

STS:

staurosporine

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Acknowledgements

We thank Abdelali Jalil and Yann Leclues (Institut Gustave Roussy, Villejuif, France) for expert assistance in confocal microscopy and FACS analysis. GK is supported by Ligue contre le Cancer and European Commission (Active p53).

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Author notes

  1. P Zhang and M Castedo: These authors contributed equally to this work.

  2. G Kroemer and Jean Bourhis: These authors are equal co-senior authors.

Authors and Affiliations

  1. UPRES-EA2710, Institut Gustave Roussy, Villejuif, France

    P Zhang, Y Tao, D Violot, E Deutsch & Jean Bourhis

  2. Centre National de la Recherche Scientifique, UMR8125, Institut Gustave Roussy, Villejuif, France

    M Castedo, D Métivier & G Kroemer

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  1. P Zhang
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  2. M Castedo
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Correspondence to G Kroemer.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Zhang, P., Castedo, M., Tao, Y. et al. Caspase independence of radio-induced cell death. Oncogene 25, 7758–7770 (2006). https://doi.org/10.1038/sj.onc.1209744

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