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. Epub 2019 Nov 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Breast Neoplasms / metabolism*
  • Carcinoma / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Extracellular Matrix / metabolism
  • Female
  • Ferritins / metabolism
  • Ferroptosis*
  • Humans
  • Iron / metabolism*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Multivesicular Bodies / metabolism
  • Phospholipid Hydroperoxide Glutathione Peroxidase / metabolism


  • Membrane Glycoproteins
  • PROM2 protein, human
  • Ferritins
  • Iron
  • Phospholipid Hydroperoxide Glutathione Peroxidase