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Acute Leukemias

Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells

Leukemia volume 27, pages 2129–2138 (2013)Cite this article

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Abstract

Previous reports demonstrate that metformin, an anti-diabetic drug, can decrease the risk of cancer and inhibit cancer cell growth. However, its mechanism in cancer cells is still unknown. Metformin significantly blocks cell cycle and inhibits cell proliferation and colony formation of leukemic cells. However, the apoptotic response to metformin varies. Furthermore, daily treatment with metformin induces apoptosis and reduces tumor growth in vivo. While metformin induces early and transient activation of AMPK, inhibition of AMPKα1/2 does not abrogate anti-proliferative or pro-apoptotic effects of metformin. Metformin decreases electron transport chain complex I activity, oxygen consumption and mitochondrial ATP synthesis, while stimulating glycolysis for ATP and lactate production, pentose phosphate pathway for purine biosynthesis, fatty acid metabolism, as well as anaplerotic and mitochondrial gene expression. Importantly, leukemic cells with high basal AKT phosphorylation, glucose consumption or glycolysis exhibit a markedly reduced induction of the Pasteur effect in response to metformin and are resistant to metformin-induced apoptosis. Accordingly, glucose starvation or treatment with deoxyglucose or an AKT inhibitor induces sensitivity to metformin. Overall, metformin elicits reprogramming of intermediary metabolism leading to inhibition of cell proliferation in all leukemic cells and apoptosis only in leukemic cells responding to metformin with AKT phosphorylation and a strong Pasteur effect.

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Acknowledgements

We thank Clément Larrue, Zhu Wang, Frédéric Lagarrigue and Drs Marion David, Christian Touriol and Stéphane Rocchi for technical assistance, and Dr Laurent Le Cam, Professor Louis Casteilla and Hugues Chap for helpful discussion and reading of the manuscript. We thank the Platform of Experimental Histophathology of INERM/UPS for technical assistance. We thank Valérie Duplan-Eche, Delphine Lestrade and Fatima L’Faqihi-Olive for technical assistance at the flow cytometry core facility of INSERM UMR1043. SS is a recipient of the American Society of Hematology Trainee Research Award and Chateaubriand Fellowship from the French Embassy at Washington DC. YM was a recipient of Fondation de France post-doctoral fellowship. MC is supported by the Veterans Affairs Administration (1I01BX000918-01) and National Institute of Health (1R01CA149566-01A1). This work was supported by grants from CHOP Mitochondrial Interest Group (J-ES), Association Laurette Fugain (J-ES) and Fondation InNaBioSanté (CR, J-ES).

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Authors and Affiliations

  1. INSERM, U1037, Cancer Research Center of Toulouse, CHU Purpan, Toulouse, France

    S Scotland, E Saland, N Skuli, F de Toni, H Boutzen, Y Martineau, T Levade, S Manenti, C Récher & J-E Sarry

  2. Université de Paul Sabatier, Toulouse III, Toulouse, France

    S Scotland, E Saland, N Skuli, F de Toni, H Boutzen, Y Martineau, T Levade, S Manenti, C Récher & J-E Sarry

  3. Department of Medicine, Division of Hematology & Oncology, University of Pennsylvania, Philadelphia, PA, USA

    E Micklow, G Danet-Desnoyers, M A Selak & M Carroll

  4. Sanofi R&D, Early-to-Candidate Unit, Toulouse, France

    I Sénégas, F Bono & N Alet

  5. Université de Toulouse, INSA, UPS, INP, LISBP, Toulouse, France

    R Peyraud, L Peyriga & J-C Portais

  6. INRA, UMR792, Ingénierie des Systèmes Biologiques et des Procédés, Toulouse, France

    R Peyraud, L Peyriga & J-C Portais

  7. CNRS, UMR5504, Toulouse, France

    L Peyriga & J-C Portais

  8. CEA/DSV/iBiTec-S/SPI, Bâtiment 136, CEA/Saclay, Fontenay-aux-Roses, Gif-sur-Yvette, France

    F Théodoro & C Junot

  9. Institut de Biochimie et Génétique Cellulaires, CNRS UMR 5095, Université de Bordeaux, Bordeaux, France

    E Dumon & C Rocher

  10. Service d'Hématologie, CHU de Toulouse, Hôpital Purpan, Toulouse, France

    C Récher

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Scotland, S., Saland, E., Skuli, N. et al. Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells. Leukemia 27, 2129–2138 (2013). https://doi.org/10.1038/leu.2013.107

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