UMMS Affiliation

Department of Molecular, Cell and Cancer Biology; Program in Molecular Medicine; Graduate School of Biomedical Sciences

Publication Date

2021-02-20

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Cancer Biology | Cell Biology | Neoplasms

Abstract

Inducers of ferroptosis such as the glutathione depleting agent Erastin and the GPX4 inhibitor Rsl-3 are being actively explored as potential therapeutics in various cancers, but the factors that determine their sensitivity are poorly understood. Here, we show that expression levels of both subunits of the cystine/glutamate antiporter xCT determine the expression of GPX4 in breast cancer, and that upregulation of the xCT/selenocysteine biosynthesis/GPX4 production axis paradoxically renders the cancer cells more sensitive to certain types of ferroptotic stimuli. We find that GPX4 is strongly upregulated in a subset of breast cancer tissues compared to matched normal samples, and that this is tightly correlated with the increased expression of the xCT subunits SLC7A11 and SLC3A2. Erastin depletes levels of the antioxidant selenoproteins GPX4 and GPX1 in breast cancer cells by inhibiting xCT-dependent extracellular reduction which is required for selenium uptake and selenocysteine biosynthesis. Unexpectedly, while breast cancer cells are resistant compared to nontransformed cells against oxidative stress inducing drugs, at the same time they are hypersensitive to lipid peroxidation and ferroptosis induced by Erastin or Rsl-3, indicating that they are 'addicted' to the xCT/GPX4 axis. Our findings provide a strategic basis for targeting the anti-ferroptotic machinery of breast cancer cells depending on their xCT status, which can be further explored.

Keywords

Erastin, GPX4; Rsl-3, breast cancer, ferroptosis, lipid peroxidation, selenium

Rights and Permissions

Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

DOI of Published Version

10.3390/antiox10020317

Source

Lee N, Carlisle AE, Peppers A, Park SJ, Doshi MB, Spears ME, Kim D. xCT-Driven Expression of GPX4 Determines Sensitivity of Breast Cancer Cells to Ferroptosis Inducers. Antioxidants (Basel). 2021 Feb 20;10(2):317. doi: 10.3390/antiox10020317. PMID: 33672555; PMCID: PMC7923775. Link to article on publisher's site

Journal/Book/Conference Title

Antioxidants (Basel, Switzerland)

Related Resources

Link to Article in PubMed

PubMed ID

33672555

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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