Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia.

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.

• Authors: Pierre Sujobert, Laury Poulain, Etienne Paubelle, Florence Zylbersztejn, Adrien Grenier, Mireille Lambert, Elizabeth C Townsend, Jean-Marie Brusq, Edwige Nicodeme, Justine Decrooqc, Ina Nepstad, Alexa S Green, Johanna Mondesir, Marie-Anne Hospital, Nathalie Jacque, Alexandra Christodoulou, Tiffany A Desouza, Olivier Hermine, Marc Foretz, Benoit Viollet, Catherine Lacombe, Patrick Mayeux, David M Weinstock, Ivan C Moura, Didier Bouscary, Jerome Tamburini
• Journal: Cell reports (Cell Rep) Vol. 11 Issue 9 Pg. 1446-57 (Jun 09 2015) ISSN: 2211-1247 [Electronic] United States
• PMID: 26004183 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• GSK621
• Imidazoles
• Multiprotein Complexes
• Pyrimidinones
• Mechanistic Target of Rapamycin Complex 1
• TOR Serine-Threonine Kinases
• AMP-Activated Protein Kinases

Topics

• 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