@article{5b7cdd24c0ed4222ad229c5502e3e29e,
title = "PDK4 dictates metabolic resistance to ferroptosis by suppressing pyruvate oxidation and fatty acid synthesis",
abstract = "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.",
keywords = "PDK4, cancer, fatty acid, ferroptosis, glucose, glycolysis, metabolism, pyruvate oxidation, resistance, therapy",
author = "Xinxin Song and Jiao Liu and Feimei Kuang and Xin Chen and Zeh, {Herbert J.} and Rui Kang and Guido Kroemer and Yangchun Xie and Daolin Tang",
note = "Funding Information: We thank Dave Primm (Department of Surgery, University of Texas Southwestern Medical Center) for critical reading of the manuscript. R.K. is supported by a grant from the National Institutes of Health ( R01CA211070 ). G.K. is supported by the Ligue Contre le Cancer ({\'e}quipe labellis{\'e}e); Agence National de la Recherche (ANR) – Projets blancs ; ANR under the frame of E-Rare-2 , the ERA-Net for Research on Rare Diseases; Association pour la recherch{\'e} sur le cancer (ARC); Canc{\'e}rop{\^o}le Ile-de-France ; Chancelerie des universit{\'e}s de Paris (Legs Poix) , Fondation pour la Recherche M{\'e}dicale (FRM); a donation by Elior ; the European Research Area Network on Cardiovascular Diseases (ERA-CVD; MINOTAUR ); Gustave Roussy Odyssea , the European Union Horizon 2020 Project Oncobiome ; Fondation Carrefour ; the High-End Foreign Expert Program in China ( GDW20171100085 and GDW20181100051 ), Institut National du Cancer (INCa); INSERM ( HTE ); Institut Universitaire de France ; the Leducq Foundation ; LabEx Immuno-Oncology ; RHU Torino Lumi{\`e}re ; the Seerave Foundation ; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalized Medicine (CARPEM). Y.X. was supported by the National Natural Science Foundation of China ( 81802476 ). Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = feb,
day = "23",
doi = "10.1016/j.celrep.2021.108767",
language = "English (US)",
volume = "34",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}