Glycolysis inhibition targets Mcl-1 to restore sensitivity of lymphoma cells to ABT-737-induced apoptosis (original) (raw)

Leukemia volume 26, pages 1145–1147 (2012)Cite this article

In its simplest description, apoptosis is a cell death process largely regulated by the Bcl-2 family that is composed of anti-apoptotic proteins (Bcl-2, Bcl-xL, Mcl-1, A1...) as opposed to pro-apoptotic members (Bax, Bak, Bim...).1 Overexpression of anti-apoptotic members is among the best-characterized cause of apoptosis resistance. The anti-apoptotic activity of some proteins of this family can now be manipulated pharmacologically, using ‘BH3-mimetic’ molecules, such as ABT-737, which inhibit the interaction with pro-apoptotic counterparts.2 Numerous phase I trials in solid and hematological cancers, including non-Hodgkin's lymphoma, are underway to assess the effects of navitoclax, an orally available BH3-mimetic. However, as it is the case with most chemotherapeutic agents, a number of cancer cells do not respond to ABT-737 mainly because this compound cannot appreciably bind to Mcl-1 or A1.2 Therefore, identifying a way to modulate the sensitivity to ABT-737 could represent an innovative method to sensitize resistant tumor cells to this agent.

To evaluate the effect of glycolysis inhibition on Mcl-1 expression, Ramos or primary Eμ-myc cells were incubated with two potent hexokinase (HK) inhibitors: 2-deoxyglucose (2DG) or Lonidamine (LND) each leading to a ∼40% reduction of lactate production (not shown). As shown in Figure 1c, 2DG and LND were able to lead to a reduction from 20 to 70% of Mcl-1 expression in Ramos as in primary Eμ-myc cells. Mcl-1 reduction was mediated through a metabolic control of its translation rates rather than a change of its stability (not shown), which is consistent with our recent publication.3

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Acknowledgements

We thank Joseph T Opferman (St Jude Children's Research Hospital) for Mcl-1−/− MEF, and greatly acknowledge the C3 M animal room facility. This work was supported in part by the Association pour la Recherche sur le Cancer (ARC) and by l’Agence Nationale de la Recherche (ANR-09-JCJC-0003-01). MB is supported by la Fondation pour la Recherche Médicale (FRM), AC is supported by ARC, MJ received a fellowship from la Région PACA, JER and MC are recipients of a contrat d’interface INSERM-CHU de Nice.

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Authors and Affiliations

  1. Inserm, U895, Centre Méditerranéen de Médecine Moléculaire (C3 M), équipe ‘controle métabolique des morts cellulaires’, Nice, Cedex, France
    O Meynet, M Bénéteau, M A Jacquin, L A Pradelli, A Cornille, M Carles & J-E Ricci
  2. Université de Nice-Sophia-Antipolis, Faculté de Médecine, Institut Signalisation et Pathologie (IFR50), Nice, France
    O Meynet, M Bénéteau, M A Jacquin, L A Pradelli, A Cornille & J-E Ricci
  3. Département d’Anesthésie Réanimation, Centre Hospitalier Universitaire de Nice, Nice, France
    M Carles & J-E Ricci

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  1. O Meynet
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  2. M Bénéteau
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  3. M A Jacquin
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  4. L A Pradelli
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  5. A Cornille
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  6. M Carles
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  7. J-E Ricci
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Correspondence toJ-E Ricci.

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Meynet, O., Bénéteau, M., Jacquin, M. et al. Glycolysis inhibition targets Mcl-1 to restore sensitivity of lymphoma cells to ABT-737-induced apoptosis.Leukemia 26, 1145–1147 (2012). https://doi.org/10.1038/leu.2011.327

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