Journal
CELL REPORTS
Volume 34, Issue 8, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.108767
Keywords
-
Categories
Funding
- National Institutes of Health [R01CA211070]
- Ligue Contre le Cancer (equipe labellisee)
- Agence National de la Recherche (ANR)
- ANR
- Association pour la recherchesur le cancer (ARC)
- Canceropole Ile-de-France
- Chancelerie des universites de Paris (Legs Poix), Fondation pour la Recherche Medicale (FRM)
- European Research Area Network on Cardiovascular Diseases (ERA-CVD
- MINOTAUR)
- Gustave Roussy Odyssea
- European Union
- Fondation Carrefour
- High-End Foreign Expert Program in China [GDW20171100085, GDW20181100051]
- Institut National du Cancer (INCa)
- INSERM
- Institut Universitaire de France
- Leducq Foundation
- LabEx Immuno-Oncology
- Seerave Foundation
- SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE)
- SIRIC Cancer Research and Personalized Medicine (CARPEM)
- National Natural Science Foundation of China [81802476]
- RHU Torino Lumiere
Ask authors/readers for more resources
Glucose determines the sensitivity of human pancreatic ductal carcinoma cells to ferroptosis and PDK4 is identified as the top gene responsible for ferroptosis resistance. Inhibiting PDK4 enhances the anticancer activity of system xc(-) inhibitors in vitro and in suitable preclinical mouse models. These findings suggest metabolic reprogramming as a potential target for overcoming ferroptosis resistance.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available