PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis
| Autor: | Xinxin Song, Xin Chen, Feimei Kuang, Daolin Tang, Herbert J. Zeh, Jiao Liu, Rui Kang, Guido Kroemer, Yangchun Xie |
|---|---|
| Přispěvatelé: | University of Texas Southwestern Medical Center, Southern Medical University [Guangzhou], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institut Gustave Roussy (IGR), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Karolinska University Hospital [Stockholm], Gestionnaire, Hal Sorbonne Université, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité) |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Small interfering RNA [SDV]Life Sciences [q-bio] Glucose uptake chemistry.chemical_compound 0302 clinical medicine Pyruvic Acid Glycolysis glucose lcsh:QH301-705.5 chemistry.chemical_classification Glucose Transporter Type 1 Fatty Acids glycolysis Cell biology [SDV] Life Sciences [q-bio] Gene Expression Regulation Neoplastic PDK4 Oxidation-Reduction Carcinoma Pancreatic Ductal Signal Transduction Pyruvate decarboxylation Antineoplastic Agents Mice Transgenic Diet High-Fat General Biochemistry Genetics and Molecular Biology resistance 03 medical and health sciences Cell Line Tumor cancer Animals Ferroptosis Humans Fatty acid synthesis therapy Fatty acid Pyruvate Dehydrogenase Acetyl-Transferring Kinase Metabolism Mice Inbred C57BL Pancreatic Neoplasms 030104 developmental biology chemistry lcsh:Biology (General) Drug Resistance Neoplasm pyruvate oxidation fatty acid Energy Metabolism metabolism 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 34, Iss 8, Pp 108767-(2021) Cell Reports Cell Reports, Elsevier Inc, 2021, 34 (8), pp.108767. ⟨10.1016/j.celrep.2021.108767⟩ Cell Reports, 2021, 34 (8), pp.108767. ⟨10.1016/j.celrep.2021.108767⟩ |
| ISSN: | 2211-1247 |
| Popis: | International audience; Although induction of ferroptosis, an iron-dependent form of non-apoptotic cell death, has emerged as an anticancer strategy, the metabolic basis of ferroptotic death remains poorly elucidated. Here, we show that glucose determines the sensitivity of human pancreatic ductal carcinoma cells to ferroptosis induced by pharmacologically inhibiting system xc-. Mechanistically, SLC2A1-mediated glucose uptake promotes glycolysis and, thus, facilitates pyruvate oxidation, fuels the tricyclic acid cycle, and stimulates fatty acid synthesis, which finally facilitates lipid peroxidation-dependent ferroptotic death. Screening of a small interfering RNA (siRNA) library targeting metabolic enzymes leads to identification of pyruvate dehydrogenase kinase 4 (PDK4) as the top gene responsible for ferroptosis resistance. PDK4 inhibits ferroptosis by blocking pyruvate dehydrogenase-dependent pyruvate oxidation. Inhibiting PDK4 enhances the anticancer activity of system xc- inhibitors in vitro and in suitable preclinical mouse models (e.g., a high-fat diet diabetes model). These findings reveal metabolic reprogramming as a potential target for overcoming ferroptosis resistance. |
| Databáze: | OpenAIRE |
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