Ferroptosis is a regulated form of lipotoxic cell death that involves iron-dependent generation of reactive oxygen species (ROS) and the accumulation of oxidatively damaged lipids (e.g. lipid peroxides). Ferroptosis has been implicated in the etiology of degenerative diseases, such as neurodegeneration associated with iron accumulation. Cells contain a protective pathway in which the glutathione-dependent peroxidase GPX4 repairs lipid peroxides and blocks cell death. Targeted induction of ferroptosis by inhibiting GPX4 has proven to be an efficacious treatment in in vitro and in vivo models of cancer, including drug-resistant forms of cancer. Despite the excitement from these recent findings, our understanding of the mechanisms underlying ferroptosis remains limited. Furthermore, many cancer cells are resistant to ferroptosis and the mechanisms of ferroptosis resistance in cancer remains mostly unknown. To overcome this critical gap in knowledge, we performed a synthetic lethal, whole-genome CRISPR screen to identify factors that protect cancer cells from ferroptosis. Our findings identify the lipid droplet oxidoreductase AIFM2 as a key factor that promotes ferroptosis resistance in cancer. Deletion of AIFM2 dramatically sensitizes cells to ferroptosis and AIFM2 levels correlate with cancer resistance across hundreds of cancer lines, indicating that AIFM2 is a biomarker of ferroptosis resistance and suggesting that it is broadly involved in ferroptosis resistance across many types of cancer. Our proposed research builds on our discovery and employs a combination of functional genomic, cell biology, and biochemistry strategies to achieve the following goals: 1) elucidate the mechanism by which AIFM2 prevents lipid damage and ferroptosis, 2) define the relationship between lipid droplets, fatty acid metabolism, and ferroptosis, and 3) identify new factors involved in protecting cancer cells from ferroptosis. These goals are potentially transformative because they focus on new mechanisms of ferroptosis resistance in cancer cells that act in parallel to the canonical glutathione-based protective system.

Public Health Relevance

Ferroptosis is a regulated form of lipotoxic cell death that has been implicated in the etiology of degenerative diseases and can be targeted to kill drug-resistant cancer cells. Our research aims to understand the mechanisms that protect cells from lipotoxicity and promote cancer resistance to ferroptosis. Our research will identify new factors that can be targeted for novel chemotherapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM112948-06
Application #
9818767
Study Section
Membrane Biology and Protein Processing Study Section (MBPP)
Program Officer
Maas, Stefan
Project Start
2014-12-01
Project End
2024-11-30
Budget Start
2019-12-10
Budget End
2020-11-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Nutrition
Type
Earth Sciences/Resources
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Bersuker, Kirill; Olzmann, James A (2018) In Close Proximity: The Lipid Droplet Proteome and Crosstalk With the Endoplasmic Reticulum. Contact (Thousand Oaks) 1:
Li, Zhipeng; Olzmann, James A (2018) A Proteomic Map to Navigate Subcellular Reorganization in Fatty Liver Disease. Dev Cell 47:139-141
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Bersuker, Kirill; Peterson, Clark W H; To, Milton et al. (2018) A Proximity Labeling Strategy Provides Insights into the Composition and Dynamics of Lipid Droplet Proteomes. Dev Cell 44:97-112.e7
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Anderson, Kimberly E; To, Milton; Olzmann, James A et al. (2017) Chemoproteomics-Enabled Covalent Ligand Screening Reveals a Thioredoxin-Caspase 3 Interaction Disruptor That Impairs Breast Cancer Pathogenicity. ACS Chem Biol 12:2522-2528
Nguyen, Truc B; Olzmann, James A (2017) Lipid droplets and lipotoxicity during autophagy. Autophagy 13:2002-2003
Bersuker, Kirill; Olzmann, James A (2017) Establishing the lipid droplet proteome: Mechanisms of lipid droplet protein targeting and degradation. Biochim Biophys Acta Mol Cell Biol Lipids 1862:1166-1177
To, Milton; Peterson, Clark W H; Roberts, Melissa A et al. (2017) Lipid disequilibrium disrupts ER proteostasis by impairing ERAD substrate glycan trimming and dislocation. Mol Biol Cell 28:270-284

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