1. AMPK-PERK axis represses oxidative metabolism and enhances apoptotic priming of mitochondria in acute myeloid leukemia
- Author
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Adrien Grenier, Laury Poulain, Johanna Mondesir, Arnaud Jacquel, Claudie Bosc, Lucille Stuani, Sarah Mouche, Clement Larrue, Ambrine Sahal, Rudy Birsen, Victoria Ghesquier, Justine Decroocq, Fetta Mazed, Mireille Lambert, Mamy Andrianteranagna, Benoit Viollet, Patrick Auberger, Andrew A. Lane, Pierre Sujobert, Didier Bouscary, Jean-Emmanuel Sarry, and Jerome Tamburini
- Subjects
Adult ,Male ,Adolescent ,THP-1 Cells ,Citric Acid Cycle ,Drug Evaluation, Preclinical ,Antineoplastic Agents ,Apoptosis ,HL-60 Cells ,Pyrimidinones ,AMP-Activated Protein Kinases ,General Biochemistry, Genetics and Molecular Biology ,Oxidative Phosphorylation ,Mice ,Young Adult ,eIF-2 Kinase ,Cell Line, Tumor ,Animals ,Humans ,Aged ,Aged, 80 and over ,Sulfonamides ,Imidazoles ,U937 Cells ,Middle Aged ,Bridged Bicyclo Compounds, Heterocyclic ,Mitochondria ,Leukemia, Myeloid, Acute ,HEK293 Cells ,Proto-Oncogene Proteins c-bcl-2 ,Unfolded Protein Response ,Female - Abstract
AMP-activated protein kinase (AMPK) regulates the balance between cellular anabolism and catabolism dependent on energy resources to maintain proliferation and survival. Small-compound AMPK activators show anti-cancer activity in preclinical models. Using the direct AMPK activator GSK621, we show that the unfolded protein response (UPR) is activated by AMPK in acute myeloid leukemia (AML) cells. Mechanistically, the UPR effector protein kinase RNA-like ER kinase (PERK) represses oxidative phosphorylation, tricarboxylic acid (TCA) cycle, and pyrimidine biosynthesis and primes the mitochondrial membrane to apoptotic signals in an AMPK-dependent manner. Accordingly, in vitro and in vivo studies reveal synergy between the direct AMPK activator GSK621 and the Bcl-2 inhibitor venetoclax. Thus, selective AMPK-activating compounds kill AML cells by rewiring mitochondrial metabolism that primes mitochondria to apoptosis by BH3 mimetics, holding therapeutic promise in AML.
- Published
- 2021