Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia
AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential...
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| Veröffentlicht in: | Cell reports (Cambridge) Jg. 11; H. 9; S. 1446 - 1457 |
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09.06.2015
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| Abstract | AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers.
[Display omitted]
•AMPK activation blocks AML propagation without toxicity to normal hematopoiesis•Cytotoxicity induced by an AMPK activator (GSK621) involves autophagy in AML•Co-activation of AMPK and mTORC1 is synthetically lethal in AML•AMPK and mTORC1 crosstalk requires eIF2α/ATF4 signaling
Sujobert et al. show that specific AMPK activation by GSK621 induces cytotoxicity in AML but not in normal hematopoietic cells. AMPK-mediated cytotoxicity indeed requires mTORC1 activation that is unique to AML cells and involves the eIF2α/ATF4 signaling pathway. This indicates a potential for AMPK-activating agents in the treatment of mTORC1-overactivated cancers. |
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| AbstractList | AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers.AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers. AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers. [Display omitted] •AMPK activation blocks AML propagation without toxicity to normal hematopoiesis•Cytotoxicity induced by an AMPK activator (GSK621) involves autophagy in AML•Co-activation of AMPK and mTORC1 is synthetically lethal in AML•AMPK and mTORC1 crosstalk requires eIF2α/ATF4 signaling Sujobert et al. show that specific AMPK activation by GSK621 induces cytotoxicity in AML but not in normal hematopoietic cells. AMPK-mediated cytotoxicity indeed requires mTORC1 activation that is unique to AML cells and involves the eIF2α/ATF4 signaling pathway. This indicates a potential for AMPK-activating agents in the treatment of mTORC1-overactivated cancers. AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers. AMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers. |
| Author | Moura, Ivan C. Desouza, Tiffany A. Hermine, Olivier Lacombe, Catherine Mayeux, Patrick Foretz, Marc Nicodeme, Edwige Sujobert, Pierre Brusq, Jean-Marie Weinstock, David M. Bouscary, Didier Jacque, Nathalie Green, Alexa S. Mondesir, Johanna Paubelle, Etienne Viollet, Benoit Lambert, Mireille Christodoulou, Alexandra Tamburini, Jerome Nepstad, Ina Townsend, Elizabeth C. Poulain, Laury Zylbersztejn, Florence Grenier, Adrien Hospital, Marie-Anne Decrooqc, Justine |
| Author_xml | – sequence: 1 givenname: Pierre surname: Sujobert fullname: Sujobert, Pierre organization: INSERM U1016, Institut Cochin, 75014 Paris, France – sequence: 2 givenname: Laury surname: Poulain fullname: Poulain, Laury organization: INSERM U1016, Institut Cochin, 75014 Paris, France – sequence: 3 givenname: Etienne surname: Paubelle fullname: Paubelle, Etienne organization: INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, 75015 Paris, France – sequence: 4 givenname: Florence surname: Zylbersztejn fullname: Zylbersztejn, Florence organization: INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, 75015 Paris, France – sequence: 5 givenname: Adrien surname: Grenier fullname: Grenier, Adrien organization: INSERM U1016, Institut Cochin, 75014 Paris, France – sequence: 6 givenname: Mireille surname: Lambert fullname: Lambert, Mireille organization: INSERM U1016, Institut Cochin, 75014 Paris, France – sequence: 7 givenname: Elizabeth C. surname: Townsend fullname: Townsend, Elizabeth C. organization: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA – sequence: 8 givenname: Jean-Marie surname: Brusq fullname: Brusq, Jean-Marie organization: GlaxoSmithKline Research Center, 91490 Les Ulis, France – sequence: 9 givenname: Edwige surname: Nicodeme fullname: Nicodeme, Edwige organization: GlaxoSmithKline Research Center, 91490 Les Ulis, France – sequence: 10 givenname: Justine surname: Decrooqc fullname: Decrooqc, Justine organization: INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, 75015 Paris, France – sequence: 11 givenname: Ina surname: Nepstad fullname: Nepstad, Ina organization: Division for Hematology, Department of Medicine, Haukeland University Hospital, N-5021 Bergen, Norway – sequence: 12 givenname: Alexa S. surname: Green fullname: Green, Alexa S. organization: INSERM U1016, Institut Cochin, 75014 Paris, France – sequence: 13 givenname: Johanna surname: Mondesir fullname: Mondesir, Johanna organization: INSERM U1016, Institut Cochin, 75014 Paris, France – sequence: 14 givenname: Marie-Anne surname: Hospital fullname: Hospital, Marie-Anne organization: INSERM U1016, Institut Cochin, 75014 Paris, France – sequence: 15 givenname: Nathalie surname: Jacque fullname: Jacque, Nathalie organization: INSERM U1016, Institut Cochin, 75014 Paris, France – sequence: 16 givenname: Alexandra surname: Christodoulou fullname: Christodoulou, Alexandra organization: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA – sequence: 17 givenname: Tiffany A. surname: Desouza fullname: Desouza, Tiffany A. organization: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA – sequence: 18 givenname: Olivier surname: Hermine fullname: Hermine, Olivier organization: INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, 75015 Paris, France – sequence: 19 givenname: Marc surname: Foretz fullname: Foretz, Marc organization: INSERM U1016, Institut Cochin, 75014 Paris, France – sequence: 20 givenname: Benoit surname: Viollet fullname: Viollet, Benoit organization: INSERM U1016, Institut Cochin, 75014 Paris, France – sequence: 21 givenname: Catherine surname: Lacombe fullname: Lacombe, Catherine organization: INSERM U1016, Institut Cochin, 75014 Paris, France – sequence: 22 givenname: Patrick surname: Mayeux fullname: Mayeux, Patrick organization: INSERM U1016, Institut Cochin, 75014 Paris, France – sequence: 23 givenname: David M. surname: Weinstock fullname: Weinstock, David M. organization: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA – sequence: 24 givenname: Ivan C. surname: Moura fullname: Moura, Ivan C. organization: INSERM UMR 1163, Laboratory of cellular and molecular mechanisms of hematological disorders and therapeutic implications, 75015 Paris, France – sequence: 25 givenname: Didier surname: Bouscary fullname: Bouscary, Didier organization: INSERM U1016, Institut Cochin, 75014 Paris, France – sequence: 26 givenname: Jerome surname: Tamburini fullname: Tamburini, Jerome email: jerome.tamburini@inserm.fr organization: INSERM U1016, Institut Cochin, 75014 Paris, France |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26004183$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | AMP-Activated Protein Kinases - metabolism Animals Antineoplastic Agents - pharmacology Enzyme Activation - drug effects Fluorescent Antibody Technique Heterografts Humans Imidazoles - pharmacology Leukemia, Myeloid, Acute - metabolism Mechanistic Target of Rapamycin Complex 1 Mice Mice, Nude Microscopy, Electron, Transmission Multiprotein Complexes - agonists Oligonucleotide Array Sequence Analysis Polymerase Chain Reaction Pyrimidinones - pharmacology RNA Interference Signal Transduction - drug effects TOR Serine-Threonine Kinases |
| Title | Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia |
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