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Apoptosis-inducing factor determines the chemoresistance of non-small-cell lung carcinomas

Oncogene volume 23, pages 6282–6291 (2004)Cite this article

Abstract

Non-small-cell lung carcinomas (NSCLCs) are resistant to the induction of apoptosis by conventional anticancer treatment. However, NSCLC cell lines are sensitive to the action of the broad protein kinase inhibitor, staurosporine (STS). In the NSCLC cell line U1810, STS induced the mitochondrial release of apoptosis-inducing factor (AIF) and cytochrome c (Cyt c) followed by activation of caspases, nuclear condensation, DNA fragmentation and finally cell death. Although preincubation of U1810 cells with the broad-spectrum caspase inhibitor z-VAD.fmk delayed the occurrence of nuclear apoptosis induced by STS, it did not impede mitochondrial alterations (such as the release of Cyt c and AIF) and cell death to occur. Moreover, the microinjection of neither Cyt c nor recombinant active caspase-3 into the cytoplasm promoted nuclear apoptosis-related changes in U1810 cells. Evaluation of the role of the caspase-independent factor AIF in STS-mediated death revealed that, upon immunodepletion of AIF, cytosols from STS-treated U1810 lost their capacity to induce nuclear condensation when incubated with isolated nuclei. In addition, microinjection of an anti-AIF antibody prevented AIF from translocating to the nuclei of STS-treated U1810 cells and reduced STS-induced cell death. Finally, although the transfection-enforced overexpression of AIF was not sufficient to induce cell death, it did enhance STS-mediated cell killing. Altogether, these results indicate that activation of caspases is not sufficient to kill U1810 cells and rather suggests an important role for the AIF-mediated mitochondrial-mediated death pathway.

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Abbreviations

AIF:

apoptosis inducing factor

Δψm:

inner mitochondrial transmembrane potential

MPT:

mitochondrial permeability transition

G3PDH:

glyceraldehyde-3-phosphate dehydrogenase

NSCLC:

non-small-cell lung carcinoma

SCLC:

small cell lung carcinoma

STS:

staurosporine

PI:

propidium iodide

PARP:

poly(ADP-ribose) polymerase

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Acknowledgements

This work was supported by grants from INSERM, Université de Lille II, ARERS (to PM), Comité du Nord Ligue contre le cancer (to PM), Swedish Cancer Society (to BZ and BJ), Stockholm Cancer Society (to BZ), and EC-RTD Grant QLK3-CT-2002-01956 (to BZ and GK). M-AG receives a fellowship from CHRU Lille. INSERM U459 belongs to IMPRT (IFR114). We thank Dr Renata R Polakowska (INSERM U 459) for critical reading of the manuscript. We especially thank Edith Dhuiege (INSERM U459) and Martial Flactif (Service commun d'imagerie cellulaire, Lille II) for technical assistance.

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Authors and Affiliations

  1. INSERM U459, Faculté de Médecine 1, Place Verdun, Lille, Cedex, France

    Miguel-Angel Gallego, Susan Tamiji, Laurent Mortier, Pierre Formstecher & Philippe Marchetti

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

    Bertrand Joseph, Therese H Hemström & Boris Zhivotovsky

  3. Centre national de la recherche scientifique, UMR8125, Institut Gustave Roussy, 39, rue Camille-Desmoulins, Villejuif, 94805, France

    Guido Kroemer

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Correspondence to Philippe Marchetti.

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Gallego, MA., Joseph, B., Hemström, T. et al. Apoptosis-inducing factor determines the chemoresistance of non-small-cell lung carcinomas. Oncogene 23, 6282–6291 (2004). https://doi.org/10.1038/sj.onc.1207835

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