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Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study

Oncogene volume 30, pages 4544–4556 (2011)Cite this article

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Abstract

To address the question of whether established or experimental anticancer chemotherapeutics can exert their cytotoxic effects by autophagy, we performed a high-content screen on a set of cytotoxic agents. We simultaneously determined parameters of autophagy, apoptosis and necrosis on cells exposed to ∼1400 compounds. Many agents induced a ‘pure’ autophagic, apoptotic or necrotic phenotype, whereas less than 100 simultaneously induced autophagy, apoptosis and necrosis. A systematic analysis of the autophagic flux induced by the most potent 80 inducers of GFP-LC3 puncta among the NCI panel agents showed that 59 among them truly induced autophagy. The remaining 21 compounds were potent inducers of apoptosis or necrosis, yet failed to stimulate an autophagic flux, which were characterized as microtubule inhibitors. Knockdown of ATG7 was efficient in preventing GFP-LC3 puncta, yet failed to attenuate cell death by the agents that induce GFP-LC3 puncta. Thus there is not a single compound that would induce cell death by autophagy in our screening, underscoring the idea that cell death is rarely, if ever, executed by autophagy in human cells.

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Acknowledgements

GK is supported by the Ligue Nationale contre le Cancer (Equipes labellisée), Agence Nationale pour la Recherche (ANR), European Commission (Active p53, Apo-Sys, ChemoRes, ApopTrain), Fondation pour la Recherche Médicale (FRM), Fondation Bettencourt-Schueller, Institut National du Cancer (INCa) and Cancéropôle Ile-de-France. SS is supported by European Commission Apo-Sys and IM is supported by La Ligue contre le Cancer.

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Authors and Affiliations

  1. INSERM, U848, Villejuif, France

    S Shen, O Kepp, M Michaud, I Martins, D Métivier, M C Maiuri & G Kroemer

  2. Université Paris Sud, Villejuif, France

    S Shen, O Kepp, M Michaud, I Martins, D Métivier & M C Maiuri

  3. Metabolomics Platform, Institut Gustave Roussy, Villejuif, France

    S Shen, O Kepp, M Michaud, I Martins, D Métivier, M C Maiuri & G Kroemer

  4. Structure, Design & Informatics, Sanofi-Aventis, Vitry-Sur-Seine, France

    H Minoux & R T Kroemer

  5. Centre de Recherche des Cordeliers, Paris, France

    G Kroemer

  6. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    G Kroemer

  7. Université Paris Descartes, Paris, France

    G Kroemer

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  1. S Shen
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Correspondence to G Kroemer.

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Shen, S., Kepp, O., Michaud, M. et al. Association and dissociation of autophagy, apoptosis and necrosis by systematic chemical study. Oncogene 30, 4544–4556 (2011). https://doi.org/10.1038/onc.2011.168

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