Kinome screen of ferroptosis reveals a novel role of ATM in regulating iron metabolism.
Repository Usage Stats
Ferroptosis is a specialized iron-dependent cell death that is associated with lethal lipid peroxidation. Modulation of ferroptosis may have therapeutic potential since it has been implicated in various human diseases as well as potential antitumor activities. However, much remains unknown about the underlying mechanisms and genetic determinants of ferroptosis. Given the critical role of kinases in most biological processes and the availability of various kinase inhibitors, we sought to systemically identify kinases essential for ferroptosis. We performed a forward genetic-based kinome screen against ferroptosis in MDA-MB-231 cells triggered by cystine deprivation. This screen identified 34 essential kinases involved in TNFα and NF-kB signaling. Unexpectedly, the DNA damage response serine/threonine kinase ATM (mutated in Ataxia-Telangiectasia) was found to be essential for ferroptosis. The pharmacological or genetic inhibition of ATM consistently rescued multiple cancer cells from ferroptosis triggered by cystine deprivation or erastin. Instead of the canonical DNA damage pathways, ATM inhibition rescued ferroptosis by increasing the expression of iron regulators involved in iron storage (ferritin heavy and light chain, FTH1 and FTL) and export (ferroportin, FPN1). The coordinated changes of these iron regulators during ATM inhibition resulted in a lowering of labile iron and prevented the iron-dependent ferroptosis. Furthermore, we found that ATM inhibition enhanced the nuclear translocation of metal-regulatory transcription factor 1 (MTF1), responsible for regulating expression of Ferritin/FPN1 and ferroptosis protection. Genetic depletion of MTF-1 abolished the regulation of iron-regulatory elements by ATM and resensitized the cells to ferroptosis. Together, we have identified an unexpected ATM-MTF1-Ferritin/FPN1 regulatory axis as novel determinants of ferroptosis through regulating labile iron levels.
Published Version (Please cite this version)10.1038/s41418-019-0393-7
Publication InfoChen, Po-Han; Wu, Jianli; Ding, Chien-Kuang Cornelia; Lin, Chao-Chieh; Pan, Samuel; Bossa, Nathan; ... Chi, Jen-Tsan (2019). Kinome screen of ferroptosis reveals a novel role of ATM in regulating iron metabolism. Cell death and differentiation. 10.1038/s41418-019-0393-7. Retrieved from https://hdl.handle.net/10161/19668.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
More InfoShow full item record
Associate Professor in Molecular Genetics and Microbiology
We are using functional genomic approaches to investigate the nutrient signaling and stress adaptations of cancer cells when exposed to various nutrient deprivations and microenvironmental stress conditions. Recently, we focus on two areas. First, we are elucidating the genetic determinants and disease relevance of ferroptosis, a newly recognized form of cell death. Second, we have identified the mammalian stringent response pathway which is highly similar to bacterial stringent response, but
Research Professor of Pharmacology & Cancer Biology
The central focus of the lab is to understand how signaling pathway architecture and integration result in specific cell fates and how these properties have been hijacked in cancer cells. In particular, we are interested in assessing the extent to which cell-to-cell heterogeneity can affect the temporal dynamics and regulation of signaling pathways. We are focusing on the E2F/Rb network and have established a platform to follow in real time the activation and expression of E2F1 at the
Alphabetical list of authors with Scholars@Duke profiles.