Ferroptosis in a new form of regulated, non-apoptotic cell death that we discovered; we have determined the major mechanisms regulating activation of ferroptosis and several contexts where it can be induced in sensitized tumors. We found that ferroptosis is ultimately characterized by excessive lipid peroxidation upon loss of activity of the lipid repair enzyme glutathione peroxidase 4 (Gpx4). We propose here the hypothesis that lipid peroxidation serves as a signal to detect a scarcity of nutrients needed tor repair of oxidative damage, and that ferroptosis serves as an innate tumor suppression mechanism to eliminate nascent tumors experiencing such oxidative stress. We further propose to elucidate mechanisms driving ferroptosis in specific cancer contexts, and whether it is feasible to create precision small molecule activators of ferroptosis that eliminate tumors that have become addicted to this repair pathway.

Public Health Relevance

The goal of the proposed research is to understand the mechanisms and translational relevance of lipid peroxidation and ferroptosis, and how these processes may naturally aid in suppressing tumor formation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
1R35CA209896-01
Application #
9185538
Study Section
Special Emphasis Panel (ZCA1-GRB-I (M2))
Program Officer
Salnikow, Konstantin
Project Start
2016-09-02
Project End
2023-07-31
Budget Start
2016-09-02
Budget End
2017-07-31
Support Year
1
Fiscal Year
2016
Total Cost
$809,277
Indirect Cost
$300,929
Name
Columbia University (N.Y.)
Department
Biology
Type
Other Domestic Higher Education
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Stockwell, Brent R; Friedmann Angeli, José Pedro; Bayir, Hülya et al. (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 171:273-285
Distéfano, Ayelén Mariana; Martin, María Victoria; Córdoba, Juan Pablo et al. (2017) Heat stress induces ferroptosis-like cell death in plants. J Cell Biol 216:463-476
Agmon, Eran; Stockwell, Brent R (2017) Lipid homeostasis and regulated cell death. Curr Opin Chem Biol 39:83-89
Gaschler, Michael M; Stockwell, Brent R (2017) Lipid peroxidation in cell death. Biochem Biophys Res Commun 482:419-425
Hayano, M; Yang, W S; Corn, C K et al. (2016) Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ 23:270-8