Mitochondrial energetic and AKT status mediate metabolic effects and apoptosis of metformin in human leukemic cells
| Autor: | Helena Boutzen, N Alet, F Théodoro, F Bono, J-E Sarry, Lindsay Peyriga, Thierry Levade, S Scotland, C Rocher, Stéphane Manenti, Gwenn-ael Danet-Desnoyers, Christian Recher, E Dumon, I Sénégas, Nicolas Skuli, Yvan Martineau, Mary A. Selak, J-C Portais, Elizabeth Micklow, Rémi Peyraud, Christophe Junot, Estelle Saland, F. De Toni, Martin Carroll |
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| Přispěvatelé: | Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées, University of Pennsylvania, Sanofi-Aventis, Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), CHU de Toulouse, Service d’Hématologie, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Chateaubriand Fellowship from French Embassy at Washington DC, Fondation de France post-doctoral fellowship, Veterans Affairs Administration [1I01BX000918-01], National Institute of Health [1R01CA149566-01A1], CHOP Mitochondrial Interest Group, Association Laurette Fugain, Fondation InNaBioSante, American Society of Hematology Trainee Research Award, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), ProdInra, Migration |
| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
endocrine system diseases [SDV]Life Sciences [q-bio] Pasteur effect Apoptosis AMP-Activated Protein Kinases Immunoenzyme Techniques Mice 0302 clinical medicine Adenosine Triphosphate [SDV.IDA]Life Sciences [q-bio]/Food engineering therapeutics Tumor Cells Cultured Glycolysis Phosphorylation RNA Small Interfering 0303 health sciences Leukemia digestive oral and skin physiology Hematology [SDV.IDA] Life Sciences [q-bio]/Food engineering Cell cycle Metformin 3. Good health Mitochondria [SDV] Life Sciences [q-bio] Oncology 030220 oncology & carcinogenesis medicine.drug medicine.medical_specialty Spectrometry Mass Electrospray Ionization [SPI.GPROC] Engineering Sciences [physics]/Chemical and Process Engineering Blotting Western Mice Nude Biology 03 medical and health sciences Oxygen Consumption Internal medicine medicine Animals Humans Hypoglycemic Agents [SPI.GPROC]Engineering Sciences [physics]/Chemical and Process Engineering Lactic Acid Protein kinase B 030304 developmental biology Cell Proliferation Cell growth nutritional and metabolic diseases Xenograft Model Antitumor Assays Endocrinology Glucose Cancer cell Cancer research metabolism Proto-Oncogene Proteins c-akt Chromatography Liquid |
| Zdroj: | Leukemia Leukemia, Nature Publishing Group: Open Access Hybrid Model Option B, 2013, 27 (11), pp.2129-2138. ⟨10.1038/leu.2013.107⟩ Leukemia, 2013, 27 (11), pp.2129-2138. ⟨10.1038/leu.2013.107⟩ |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/leu.2013.107⟩ |
| Popis: | International audience; 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 AMPK alpha 1/2 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. |
| Databáze: | OpenAIRE |
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