Oxidative Phosphorylation Fueled by Fatty Acid Oxidation Sensitizes Leukemic Stem Cells to Cold.

Autor:	Griessinger E; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.; Université Côte d'Azur, INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France., Pereira-Martins D; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Nebout M; Université Côte d'Azur, INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France., Bosc C; Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Institut National de la Santé et de la Recherché Médicale, Centre National de la Recherche Scientifique, Toulouse, France.; LabEx Toucan, Toulouse, France.; Equipe Labellisée Ligue Nationale Contre le Cancer 2018, Toulouse, France., Saland E; Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Institut National de la Santé et de la Recherché Médicale, Centre National de la Recherche Scientifique, Toulouse, France.; LabEx Toucan, Toulouse, France.; Equipe Labellisée Ligue Nationale Contre le Cancer 2018, Toulouse, France., Boet E; Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Institut National de la Santé et de la Recherché Médicale, Centre National de la Recherche Scientifique, Toulouse, France.; LabEx Toucan, Toulouse, France.; Equipe Labellisée Ligue Nationale Contre le Cancer 2018, Toulouse, France., Sahal A; Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Institut National de la Santé et de la Recherché Médicale, Centre National de la Recherche Scientifique, Toulouse, France.; LabEx Toucan, Toulouse, France.; Equipe Labellisée Ligue Nationale Contre le Cancer 2018, Toulouse, France., Chiche J; Université Côte d'Azur, INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France.; Equipe labellisée Ligue Contre le Cancer, Nice, France., Debayle D; Université Côte d'Azur, CNRS, IPMC, Valbonne, France., Fleuriot L; Université Côte d'Azur, CNRS, IPMC, Valbonne, France., Pruis M; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., De Mas V; Service d'Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, Toulouse, France., Vergez F; Service d'Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, Toulouse, France., Récher C; Service d'Hématologie, Institut Universitaire du Cancer de Toulouse-Oncopole, CHU de Toulouse, Toulouse, France., Huls G; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Sarry JE; Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Institut National de la Santé et de la Recherché Médicale, Centre National de la Recherche Scientifique, Toulouse, France.; LabEx Toucan, Toulouse, France.; Equipe Labellisée Ligue Nationale Contre le Cancer 2018, Toulouse, France., Schuringa JJ; Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Peyron JF; Université Côte d'Azur, INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Nice, France.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2023 Aug 01; Vol. 83 (15), pp. 2461-2470.
DOI:	10.1158/0008-5472.CAN-23-1006
Abstrakt:	Dependency on mitochondrial oxidative phosphorylation (OxPhos) is a potential weakness for leukemic stem cells (LSC) that can be exploited for therapeutic purposes. Fatty acid oxidation (FAO) is a crucial OxPhos-fueling catabolic pathway for some acute myeloid leukemia (AML) cells, particularly chemotherapy-resistant AML cells. Here, we identified cold sensitivity at 4°C (cold killing challenge; CKC4), commonly used for sample storage, as a novel vulnerability that selectively kills AML LSCs with active FAO-supported OxPhos while sparing normal hematopoietic stem cells. Cell death of OxPhos-positive leukemic cells was induced by membrane permeabilization at 4°C; by sharp contrast, leukemic cells relying on glycolysis were resistant. Forcing glycolytic cells to activate OxPhos metabolism sensitized them to CKC4. Lipidomic and proteomic analyses showed that OxPhos shapes the composition of the plasma membrane and introduces variation of 22 lipid subfamilies between cold-sensitive and cold-resistant cells. Together, these findings indicate that steady-state energy metabolism at body temperature predetermines the sensitivity of AML LSCs to cold temperature, suggesting that cold sensitivity could be a potential OxPhos biomarker. These results could have important implications for designing experiments for AML research to avoid cell storage at 4°C. Significance: Mitochondrial metabolism fueled by FAO alters the membrane composition and introduces membrane fragility upon cold exposure in OxPhos-driven AML and in LSCs. See related commentary by Jones, p. 2441. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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