Tumor cells are 'addicted'to high levels of the transition element iron, which is necessary for the function of iron-dependent enzymes that enable rapid tumor cell division and growth. When improperly sequestered, iron is highly redox active and can catalyze the formation of toxic reactive oxygen species that destroy the cell. It should therefore be possible to kill tumor cells in a selective way by unleashing the redox activity of this element. RAS-RAF-MEK pathway activation is a common event in many cancers that is currently difficult to treat with existing drugs. We previously identified several small molecule compounds that selectively kill a variety of human tumor cells with activating mutations in this pathway. These RAS-selective lethal (RSL) compounds appear to trigger a new form of cell death that exploits the high levels of intracellular iron found in these tumor cells. Here I focus on the lethal mechanism of one RSL, erastin. Using RNA interference (RNAi) screening I identified 11 genes required for erastin-induced death, including the uncharacterized gene ACSF2. I hypothesize that ACSF2 regulates the production of an iron-binding molecule (siderophore) that is necessary for rapid tumor cell proliferation and for the lethal effects of erastin, via regulation of cytosolic iron levels and heme-dependent NADPH oxidase 1 (NOX1) complex activity. I will test this hypothesis in human tumor cells and in Acsf2 knockout mice using genetic, biochemical and chemical assays of cell death, iron metabolism, NOX activity, siderophore production and xenograft tumor growth. This work will define the novel cell death pathway triggered by erastin and similar compounds, provide insight into the role of siderophore-mediated iron uptake in tumor cell growth and significantly improve our ability to target cellular iron addiction to achieve tumor-selective cell death in RAS pathway mutant cancers.

Public Health Relevance

The proposed studies will determine how a new class of candidate anti-tumor drugs exploit the high levels of iron found in many tumor cells to selectively kill these cells. This knowledge will open the way to new therapeutic approaches and improve our understanding of the role of iron in tumor cell life and death.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Salnikow, Konstantin
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Stanford University
Schools of Arts and Sciences
United States
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Inde, Zintis; Dixon, Scott J (2018) The impact of non-genetic heterogeneity on cancer cell death. Crit Rev Biochem Mol Biol 53:99-114
Tarangelo, Amy; Magtanong, Leslie; Bieging-Rolett, Kathryn T et al. (2018) p53 Suppresses Metabolic Stress-Induced Ferroptosis in Cancer Cells. Cell Rep 22:569-575
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
Forcina, Giovanni C; Conlon, Megan; Wells, Alex et al. (2017) Systematic Quantification of Population Cell Death Kinetics in Mammalian Cells. Cell Syst 4:600-610.e6
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
Shimada, Kenichi; Skouta, Rachid; Kaplan, Anna et al. (2016) Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol 12:497-503
Cao, Jennifer Yinuo; Dixon, Scott J (2016) Mechanisms of ferroptosis. Cell Mol Life Sci 73:2195-209
Magtanong, L; Ko, P J; Dixon, S J (2016) Emerging roles for lipids in non-apoptotic cell death. Cell Death Differ 23:1099-109
Dixon, Scott J; Winter, Georg E; Musavi, Leila S et al. (2015) Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death. ACS Chem Biol 10:1604-9
Skouta, Rachid; Dixon, Scott J; Wang, Jianlin et al. (2014) Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc 136:4551-6

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