2. Academic Validation
  3. A Genome-wide Haploid Genetic Screen Identifies Regulators of Glutathione Abundance and Ferroptosis Sensitivity

A Genome-wide Haploid Genetic Screen Identifies Regulators of Glutathione Abundance and Ferroptosis Sensitivity

  • Cell Rep. 2019 Feb 5;26(6):1544-1556.e8. doi: 10.1016/j.celrep.2019.01.043.
Jennifer Yinuo Cao 1,  Aunoy Poddar 1,  Leslie Magtanong 1,  Jennifer H Lumb 2,  Trevor R Mileur 1,  Michael A Reid 3,  Cole M Dovey 2,  Jin Wang 4,  Jason W Locasale 3,  Everett Stone 5,  Susan P C Cole 6,  Jan E Carette 2,  Scott J Dixon 7
Affiliations

Affiliations

  • 1 Department of Biology, Stanford University, Stanford, CA 94305, USA.
  • 2 Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
  • 3 Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
  • 4 Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5 Department of Molecular Biosciences, University of Texas at Austin, Austin, TX 78712, USA.
  • 6 Department of Pathology and Molecular Medicine and Division of Cancer Biology and Genetics, Queen's University, Kingston, ON K7L 3N6, Canada.
  • 7 Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: sjdixon@stanford.edu.
PMID: 30726737 DOI: 10.1016/j.celrep.2019.01.043
Abstract

The tripeptide glutathione suppresses the iron-dependent, non-apoptotic cell death process of Ferroptosis. How glutathione abundance is regulated in the cell and how this regulation alters Ferroptosis sensitivity is poorly understood. Using genome-wide human haploid genetic screening technology coupled to fluorescence-activated cell sorting (FACS), we directly identify genes that regulate intracellular glutathione abundance and characterize their role in Ferroptosis regulation. Disruption of the ATP binding cassette (ABC)-family transporter multidrug resistance protein 1 (MRP1) prevents glutathione efflux from the cell and strongly inhibits Ferroptosis. High levels of MRP1 expression decrease sensitivity to certain pro-apoptotic chemotherapeutic drugs, while collaterally sensitizing to all tested pro-ferroptotic agents. By contrast, disruption of KEAP1 and NAA38, leading to the stabilization of the transcription factor NRF2, increases glutathione levels but only weakly protects from Ferroptosis. This is due in part to concomitant NRF2-mediated upregulation of MRP1. These results pinpoint glutathione efflux as an unanticipated regulator of Ferroptosis sensitivity.

Keywords

ROS; cancer; collateral sensitivity; ferroptosis; glutathione; iron; metabolite efflux; multidrug resistance; necrosis.

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