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Prominin2 Drives Ferroptosis Resistance by Stimulating Multivesicular Body/Exosome-Mediated Iron Export

43 Pages Posted: 3 Jul 2019 Sneak Peek Status: Review Complete

See all articles by Caitlin W. Brown

Caitlin W. Brown

University of Massachusetts Worcester - Department of Molecular, Cell and Cancer Biology

John J. Amante

University of Massachusetts Worcester - Department of Molecular, Cell and Cancer Biology

Peter Chhoy

University of Massachusetts Worcester - Department of Molecular, Cell and Cancer Biology

Ameer L. Elaimy

University of Massachusetts Worcester - Department of Molecular, Cell and Cancer Biology

Liu Haibo

University of Massachusetts Worcester - Department of Molecular, Cell and Cancer Biology

Lihua Julie Zhu

University of Massachusetts Worcester - Department of Molecular, Cell and Cancer Biology

Christina E. Baer

University of Massachusetts Worcester

Scott J. Dixon

Stanford University - Department of Biology

Arthur M. Mercurio

University of Massachusetts Worcester - Department of Molecular, Cell and Cancer Biology

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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 multi-vesicular 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 they have broad implications for iron homeostasis, intracellular trafficking, and cancer.

Keywords: ferroptosis, prominin2, iron, multivesicular body, exosome

Suggested Citation

Brown, Caitlin W. and Amante, John J. and Chhoy, Peter and Elaimy, Ameer L. and Haibo, Liu and Zhu, Lihua Julie and Baer, Christina E. and Dixon, Scott J. and Mercurio, Arthur M., Prominin2 Drives Ferroptosis Resistance by Stimulating Multivesicular Body/Exosome-Mediated Iron Export (July 3, 2019). DEVELOPMENTAL-CELL-D-19-00547. Available at SSRN: https://ssrn.com/abstract=3413894 or http://dx.doi.org/10.2139/ssrn.3413894
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Caitlin W. Brown

University of Massachusetts Worcester - Department of Molecular, Cell and Cancer Biology

55 N Lake Avenue
Worcester, MA 01605
United States

John J. Amante

University of Massachusetts Worcester - Department of Molecular, Cell and Cancer Biology ( email )

55 N Lake Avenue
Worcester, MA 01605
United States

Peter Chhoy

University of Massachusetts Worcester - Department of Molecular, Cell and Cancer Biology ( email )

55 N Lake Avenue
Worcester, MA 01605
United States

Ameer L. Elaimy

University of Massachusetts Worcester - Department of Molecular, Cell and Cancer Biology ( email )

55 N Lake Avenue
Worcester, MA 01605
United States

Liu Haibo

University of Massachusetts Worcester - Department of Molecular, Cell and Cancer Biology

55 N Lake Avenue
Worcester, MA 01605
United States

Lihua Julie Zhu

University of Massachusetts Worcester - Department of Molecular, Cell and Cancer Biology

55 N Lake Avenue
Worcester, MA 01605
United States

Christina E. Baer

University of Massachusetts Worcester

55 N Lake Ave
Worcester, MA 01655
United States

Scott J. Dixon

Stanford University - Department of Biology ( email )

Gilbert Building, Rm 109
371 Serra Mall
Stanford, CA 94305
United States

Arthur M. Mercurio (Contact Author)

University of Massachusetts Worcester - Department of Molecular, Cell and Cancer Biology ( email )

55 N Lake Avenue
Worcester, MA 01605
United States

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