Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Induction of Oxidative Stress and Ferroptosis in Triple-Negative Breast Cancer Cells by Niclosamide via Blockade of the Function and Expression of SLC38A5 and SLC7A11

Marilyn Mathew
,
Sathish Sivaprakasam
ORCID logo ,
Gunadharini Dharmalingam-Nandagopal
,
Souad R. Sennoune
,
Nhi T. Nguyen
,
Valeria Jaramillo-Martinez
ORCID logo ,
Yangzom D. Bhutia
,
Vadivel Ganapathy
*
Version 1 : Received: 30 November 2023 / Approved: 30 November 2023 / Online: 30 November 2023 (10:44:16 CET)

A peer-reviewed article of this Preprint also exists.

Mathew, M.; Sivaprakasam, S.; Dharmalingam-Nandagopal, G.; Sennoune, S.R.; Nguyen, N.T.; Jaramillo-Martinez, V.; Bhutia, Y.D.; Ganapathy, V. Induction of Oxidative Stress and Ferroptosis in Triple-Negative Breast Cancer Cells by Niclosamide via Blockade of the Function and Expression of SLC38A5 and SLC7A11. Antioxidants 2024, 13, 291, doi:10.3390/antiox13030291. Mathew, M.; Sivaprakasam, S.; Dharmalingam-Nandagopal, G.; Sennoune, S.R.; Nguyen, N.T.; Jaramillo-Martinez, V.; Bhutia, Y.D.; Ganapathy, V. Induction of Oxidative Stress and Ferroptosis in Triple-Negative Breast Cancer Cells by Niclosamide via Blockade of the Function and Expression of SLC38A5 and SLC7A11. Antioxidants 2024, 13, 291, doi:10.3390/antiox13030291.

Abstract

The amino acid transporters SLC38A5 and SLC7A11 are upregulated in triple-negative breast cancer (TNBC). SLC38A5 transports glutamine, methionine, glycine and serine, and therefore activates mTOR signaling and induces epigenetic modifications. SLC7A11 transports cystine and increases cellular levels of glutathione, which protects against oxidative stress and lipid peroxidation via glutathione peroxidase, a seleno (Se)-enzyme. The primary source of Se is dietary Se-methionine (Se-Met). Since SLC38A5 transports methionine, we examined its role in Se-Met uptake in TNBC cells. We found that SLC38A5 interacts with methionine and Se-Met with comparable affinity. We also examined the influence of Se-Met on Nrf2 in TNBC cells. Se-Met activated Nrf2 and induced expression of Nrf2-target genes, including SLC7A11. Our previous work discovered niclosamide, an antiparasitic drug, as a potent inhibitor of SLC38A5. Here we found SLC7A11 to be inhibited by niclosamide with an IC50 value in the range of 0.1-0.2 M. In addition to the direct inhibition of SLC38A5 and SLC7A11, pretreatment of TNBC cells with niclosamide reduced the expression of both transporters. Niclosamide decreased glutathione levels, inhibited proliferation, suppressed GPX4 expression, increased lipid peroxidation, and induced ferroptosis in TNBC cells. It also significantly reduced the growth of the TNBC cell line MB231 in mouse xenografts.

Keywords

SLC38A5; SLC7A11; TNBC cells; seleno-methionine; glutathione; glutathione peroxidase; Nrf2; ferroptosis; lipid peroxidation; niclosamide

Subject

Medicine and Pharmacology, Endocrinology and Metabolism

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Download PDF

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0
Metrics 0
Get PDF Cite Share 0
Bookmark BibSonomy Mendeley Reddit Delicious
×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.