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  • Original Paper
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Oxaliplatin-induced mitochondrial apoptotic response of colon carcinoma cells does not require nuclear DNA

Oncogene volume 23, pages 7449–7457 (2004)Cite this article

Abstract

We previously established a model of acquired oxaliplatin resistance derived from the HCT116 oxaliplatin-sensitive cell line (HCT116S) and consisting in two resistant clones (HCT116R1, HCT116R2) and their total or partial revertants (HCT116Rev1 and HCT116Rev2, respectively). Using this cellular model, we explored the contribution of mitochondrial apoptosis and nuclear DNA to oxaliplatin-mediated apoptosis induction and oxaliplatin resistance. We showed that the activity of oxaliplatin is mediated by the induction of Bax/Bak-dependent mitochondrial apoptosis and that oxaliplatin resistance is mediated by a defect in Bax/Bak activation correlating with a reduced loss of the mitochondrial transmembrane potential (ΔΨm). In addition, we observed that p53 only contributed marginally to oxaliplatin-induced cytotoxicity and was not involved in oxaliplatin resistance. Moreover and surprisingly, depletion of the nucleus in HCT116S cells did not abolish the oxaliplatin-induced ΔΨm loss indicative of imminent apoptosis. Enucleation abolished the oxaliplatin resistance of HCT116R1 cells, while HCT116R2 cytoplasts conserved their resistant phenotype. Altogether, these data demonstrate that oxaliplatin exerts its cytotoxic effects by inducing mitochondrial apoptosis and that these effects can be initiated by interacting on other cellular structures than nuclear DNA. Resistance to oxaliplatin may imply both nuclear and cytoplasmic compartments.

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Abbreviations

Cyt:

cytochrome c

GAPDH :

glyceraldehyde-3-phosphate dehydrogenase

PFT:

cyclic pifithrin-α

ΔΨm:

mitochondrial transmembrane potential

L-OHP:

oxaliplatin

CPT11:

irinotecan

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Acknowledgements

We thank Dr B Vogelstein (John Hopkins Hospital, Baltimore, MA) for kindly providing HCT116/p53−/− and HCT116/Bax−/− cell lines, Dr P Roux (CNRS-UPR1086, Montpellier, France) for his generous gift of pGL2B-mdm2-luciferase and pTKRL plasmids and D Métivier (Institut Gustave Roussy, Villejuif, France) for his expert help in cytofluorometry. This work has been supported by a special grant from Institut Pasteur, as well as grants from LNC and the European Commission (QLK3-CT-20002-01956).

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Authors and Affiliations

  1. CNRS-UMR 8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, Villejuif, F-94805, France

    Isabelle Gourdier, Karine Andreau & Guido Kroemer

  2. Institut Pasteur, Paris, France

    Isabelle Gourdier

  3. CNRS-UMR 5160, Montpellier, France

    Laure Crabbe & Bernard Pau

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  1. Isabelle Gourdier
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Correspondence to Guido Kroemer.

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Gourdier, I., Crabbe, L., Andreau, K. et al. Oxaliplatin-induced mitochondrial apoptotic response of colon carcinoma cells does not require nuclear DNA. Oncogene 23, 7449–7457 (2004). https://doi.org/10.1038/sj.onc.1208047

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