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Targeting Tumor Cell Iron Addiction to Achieve Tumor-Selective Cell Death

Scott Dixon

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National Institutes of Health (NIH)
Tumor cells are 'addicted' to high levels of the transition element iron, which is necessary for the function ofiron-dependent enzymes that enable rapid tumor cell division and growth. When improperly sequestered, ironis highly redox active and can catalyze the formation of toxic reactive oxygen species that destroy the cell. Itshould therefore be possible to kill tumor cells in a selective way by unleashing the redox activity of thiselement. 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 avariety 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 inthese 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 necessaryfor rapid tumor cell proliferation and for the lethal effects of erastin, via regulation of cytosolic iron levels andheme-dependent NADPH oxidase 1 (NOX1) complex activity. I will test this hypothesis in human tumor cellsand 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 deathpathway triggered by erastin and similar compounds, provide insight into the role of siderophore-mediated ironuptake in tumor cell growth and significantly improve our ability to target cellular iron addiction to achievetumor-selective cell death in RAS pathway mutant cancers.

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