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Overcoming chemoresistance of non-small cell lung carcinoma through restoration of an AIF-dependent apoptotic pathway

Oncogene volume 27, pages 1981–1992 (2008)Cite this article

Abstract

Non-small cell lung carcinomas (NSCLCs) are typically resistant against apoptosis induced by standard chemotherapy. We evaluated the effects of the two potential antitumor agents of the lamellarin class on a highly apoptosis-resistant NSCLC cell line. Both the marine alkaloid lamellarin-D and its synthetic amino derivative PM031379 induced the activation of Bax, the mitochondrial release of cytochrome c and apoptosis-inducing factor (AIF), as well as the activation of caspase-3. However, only PM031379 triggered cell death and sign of nuclear apoptosis coupled to the nuclear translocation of AIF. Depletion of AIF with small interfering RNA or microinjection of a neutralizing anti-AIF antibody largely prevented PM031379-induced cytotoxicity, underscoring the essential contribution of AIF to NSCLC killing. Using NSCLC cells lacking mitochondrial DNA, we showed that the generation of mitochondrial reactive oxygen species (ROS) was crucial for the PM031379-induced translocation of AIF to the nucleus and subsequently cell death. Pretreatment of NSCLC cells with menadione, a mitochondrial ROS generator, was able to restore the deficient chemotherapy-induced apoptosis of NSCLC cells. Altogether, these data suggest that mitochondrial ROS generation is crucial for overriding the chemoresistance of NSCLC cells. Moreover, this study delineates the unique mechanism of action of lamellarins as potential anticancer agents.

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Abbreviations

AIF:

apoptosis-inducing factor

Cyt c:

cytochrome c

HE:

hydroethidine

Lam-D:

lamellarin-D

NAC:

N-acetyl cystein

NSCLC:

non-small cell lung carcinoma

ROS:

reactive oxygen species

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Acknowledgements

We thank Pierre Cappy for technical help. In memoriam we like to acknowledge the contribution to this article from Martial Flactif who passed away in July 2006.

This work was supported by grants from INSERM, Université de Lille II, Ligue Nationale contre le Cancer Comité du nord (to PM), Ligue Nationale contre le Cancer (Equipe labellisée) and Institut National contre le Cancer, and European Union ChemoRes (to GK).

Author information

Author notes

  1. C Bailly

    Present address: 6Current address: Institut de Recherche Pierre Fabre, 3 rue des satellites, 31432 Toulouse, France.,

  2. M-A Gallego and C Ballot: These authors contributed equally to this work

Authors and Affiliations

  1. INSERM U 837, Université Lille 2, Faculté de Médecine, Jean-Pierre Aubert Research Centre, Place de Verdun, Lille, France

    M-A Gallego, C Ballot, J Kluza, A Martoriati, L Castéra, P Formstecher, C Bailly & P Marchetti

  2. Institute of Environmental Medicine Karolinska Institutet, Stockholm, Sweden

    N Hajji & B Joseph

  3. PharmaMar, Avda. de los Reyes,1, P.I. La Mina-Norte, E-28770 Colmenar Viejo, Madrid, Spain

    C Cuevas

  4. INSERM U848, Institut Gustave Roussy, Villejuif, France

    G Kroemer

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  1. M-A Gallego
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Correspondence to P Marchetti.

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Gallego, MA., Ballot, C., Kluza, J. et al. Overcoming chemoresistance of non-small cell lung carcinoma through restoration of an AIF-dependent apoptotic pathway. Oncogene 27, 1981–1992 (2008). https://doi.org/10.1038/sj.onc.1210833

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