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Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation

Oncogene volume 29, pages 1641–1652 (2010)Cite this article

Abstract

Most cancer cells exhibit increased glycolysis for generation of their energy supply. This specificity could be used to preferentially kill these cells. In this study, we identified the signaling pathway initiated by glycolysis inhibition that results in sensitization to death receptor (DR)-induced apoptosis. We showed, in several human cancer cell lines (such as Jurkat, HeLa, U937), that glucose removal or the use of nonmetabolizable form of glucose (2-deoxyglucose) dramatically enhances apoptosis induced by Fas or by tumor necrosis factor-related apoptosis-inducing ligand. This sensitization is controlled through the adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is the central energy-sensing system of the cell. We established the fact that AMPK is activated upon glycolysis block resulting in mammalian target of rapamycin (mTOR) inhibition leading to Mcl-1 decrease, but no other Bcl-2 anti-apoptotic members. Interestingly, we determined that, upon glycolysis inhibition, the AMPK–mTOR pathway controlled Mcl-1 levels neither through transcriptional nor through posttranslational mechanism but rather by controlling its translation. Therefore, our results show a novel mechanism for the sensitization to DR-induced apoptosis linking glucose metabolism to Mcl-1 downexpression. In addition, this study provides a rationale for the combined use of DR ligands with AMPK activators or mTOR inhibitors in the treatment of human cancers.

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Acknowledgements

We thank Magali Herrant for her input, Audrey Paul and Céline Gracia for their technical assistance, Issam Ben Sahra, Vanessa Lavallard and Drs Anne-Odile Hueber, Frederic Bost, Stephane Rocchi and Marcel Deckert for providing tools and advises, Dr Ulrich Maurer for providing GSK3 inhibitor and Dr DR Green for Bcl-2 overexpressing Jurkat cells. This study was supported by the Association pour la Recherche sur le Cancer and by l'Agence Nationale de la Recherche (ref ANR-09-JCJC-0003-01). LAP and MAJ received a fellowship from the Conseil régional Provence-Alpes-Cote-d'Azur. MB is supported by a fellowship from La Fondation de France, CM-P is supported by the Fondo de Investigaciones Sanitarias of Spain and J-ER is a recipient of a contrat d'interface INSERM-CHU de Nice.

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Authors and Affiliations

  1. Inserm, U895, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe 3 - AVENIR, Nice, France

    L A Pradelli, M Bénéteau, M A Jacquin & J-E Ricci

  2. Université de Nice-Sophia-Antipolis, Faculté de Médecine, Nice, France

    L A Pradelli, M Bénéteau, M A Jacquin, S Marchetti, P Auberger & J-E Ricci

  3. INSERM, U845, Paris, France

    C Chauvin & M Pende

  4. Université Paris Descartes, Faculté de Médecine, UMRS-845, Paris, France

    C Chauvin & M Pende

  5. Centre d'Oncologia Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain

    C Muñoz-Pinedo

  6. Inserm, U895, Centre Méditerranéen de Médecine Moléculaire (C3M), équipe 2, Nice, France

    S Marchetti & P Auberger

  7. département d'Anesthésie Réanimation, Centre Hospitalier Universitaire de Nice, Nice, France

    J-E Ricci

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  1. L A Pradelli
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  2. M Bénéteau
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Correspondence to J-E Ricci.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Pradelli, L., Bénéteau, M., Chauvin, C. et al. Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation. Oncogene 29, 1641–1652 (2010). https://doi.org/10.1038/onc.2009.448

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