2. Academic Validation
  3. Prominin2 Drives Ferroptosis Resistance by Stimulating Iron Export

Prominin2 Drives Ferroptosis Resistance by Stimulating Iron Export

  • Dev Cell. 2019 Dec 2;51(5):575-586.e4. doi: 10.1016/j.devcel.2019.10.007.
Caitlin W Brown 1,  John J Amante 1,  Peter Chhoy 1,  Ameer L Elaimy 1,  Haibo Liu 1,  Lihua Julie Zhu 1,  Christina E Baer 2,  Scott J Dixon 3,  Arthur M Mercurio 4
Affiliations

Affiliations

  • 1 Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • 2 Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA; Sanderson Center for Optical Examination, University of Massachusetts Medical School, Worcester, MA 01605, USA.
  • 3 Department of Biology, Stanford University, Stanford, CA, USA.
  • 4 Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: arthur.mercurio@umassmed.edu.
PMID: 31735663 DOI: 10.1016/j.devcel.2019.10.007
Abstract

Ferroptosis, regulated cell death characterized by the iron-dependent accumulation of lethal lipid Reactive Oxygen Species, contributes to tissue homeostasis and numerous pathologies, and it may be exploited for therapy. Cells differ in their sensitivity to Ferroptosis, however, and a key challenge is to understand mechanisms that contribute to resistance. Using RNA-seq to identify genes that contribute to Ferroptosis resistance, we discovered that pro-ferroptotic stimuli, including inhibition of the lipid hydroperoxidase GPX4 and detachment from the extracellular matrix, induce expression of prominin2, a pentaspanin protein implicated in regulation of lipid dynamics. Prominin2 facilitates Ferroptosis resistance in mammary epithelial and breast carcinoma cells. Mechanistically, prominin2 promotes the formation of ferritin-containing multivesicular bodies (MVBs) and exosomes that transport iron out of the cell, inhibiting Ferroptosis. These findings reveal that Ferroptosis resistance can be driven by a prominin2-MVB-exosome-ferritin pathway and have broad implications for iron homeostasis, intracellular trafficking, and Cancer.

Keywords

GPX4; breast cancer; exosome; ferritin; ferroptosis; iron; mammary gland; multivesicular body; prominin2; therapy.

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