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Mitochondrial dysfunction is an essential step for killing of non-small cell lung carcinomas resistant to conventional treatment

Oncogene volume 21, pages 65–77 (2002)Cite this article

A Corrigendum to this article was published on 10 April 2017

Abstract

Apoptosis, a tightly controlled multi-step mechanism of cell death, is important for anti-cancer therapy-based elimination of tumor cells. However, this process is not always efficient. Small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) cells display different susceptibility to undergo apoptosis induced by anticancer treatment. In contrast to SCLC, NSCLC cells are cross-resistant to a broad spectrum of apoptotic stimuli, including receptor stimulation, cytotoxic drugs and γ-radiation. Since resistance of tumor cells to treatment often accounts for the failure of traditional forms of cancer therapy, in the present study attempts to find a potent broad-range apoptosis inductor, which can kill therapy-resistant NSCLC cells were undertaken and the mechanism of apoptosis induction by this drug was investigated in detail. We found that staurosporine (STS) had cell killing effect on both types of lung carcinomas. Release of cytochrome c, activation of apical and effector caspases followed by cleavage of their nuclear substrates and morphological changes specific for apoptosis were observed in STS-treated cells. In contrast to treatment with radiation or chemotherapy drugs, STS induces mitochondrial dysfunction followed by translocation of AIF into the nuclei. These events preceded the activation of nuclear apoptosis. Thus, in lung carcinomas two cell death pathways, caspase-dependent and caspase-independent, coexist. In NSCLC cells, where the caspase-dependent pathway is less efficient, the triggering of an AIF-mediated caspase-independent mechanism circumvents the resistance of these cells to treatment.

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Acknowledgements

The authors are very grateful to Prof Sten Orrenius for support and Drs R Jemmerson and PH Kramer for providing antibodies. This work was supported by grants from the Swedish Cancer Society (3829-B98-03XAC), the Stockholm Cancer Society (98:119) and INSERM-MRC. B Joseph was supported by a Fellowship from Association de Recherche contre le Cancer.

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Author notes

  1. Bertrand Joseph

    Present address: Ludwig Institute for Cancer Research, Karolinska Institutet, Box 240, S-171 77, Stockholm, Sweden

Authors and Affiliations

  1. Department of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, S-171 77, Stockholm, Sweden

    Bertrand Joseph & Boris Zhivotovsky

  2. Institut National de la Santé et de la Recherche Médicale U459, Faculté de Médecine, Lille Cedex, France

    Philippe Marchetti & Pierre Formstecher

  3. Centre National de la Recherche Scientifique, CNRS-ULR1599, Institut Gustave Roussy, 24 rue Calmette Desmoulins, Villejuif, 94805, France

    Guido Kroemer

  4. Unit of Medical Radiobiology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, S-171 76, Sweden

    Rolf Lewensohn

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Correspondence to Boris Zhivotovsky.

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Joseph, B., Marchetti, P., Formstecher, P. et al. Mitochondrial dysfunction is an essential step for killing of non-small cell lung carcinomas resistant to conventional treatment. Oncogene 21, 65–77 (2002). https://doi.org/10.1038/sj.onc.1205018

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