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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
4R00CA166517-03
Application #
8773654
Study Section
Special Emphasis Panel (NSS)
Program Officer
Salnikow, Konstantin
Project Start
2014-01-01
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
3
Fiscal Year
2014
Total Cost
$224,100
Indirect Cost
$84,474
Name
Stanford University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Dixon, Scott J; Patel, Darpan N; Welsch, Matthew et al. (2014) Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 3:e02523
Dixon, Scott J; Stockwell, Brent R (2014) The role of iron and reactive oxygen species in cell death. Nat Chem Biol 10:9-17