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Glutathione peroxidase 4 inhibition induces ferroptosis and mTOR pathway suppression in thyroid cancer

Papillary thyroid carcinoma (PTC) demonstrates significantly reduced patient survival with metastatic progression. Tumor progression can be influenced by metabolism, including antioxidant glutathione (GSH). Glutathione peroxidase 4 (GPX4) is a selenoenzyme that uses GSH as a co-factor to regulate li...

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Autores principales: Sekhar, Konjeti R., Hanna, David N., Cyr, Sriram, Baechle, Jordan J., Kuravi, Sudhakiranmayi, Balusu, Ramesh, Rathmell, Kimryn, Baregamian, Naira
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9653479/
https://www.ncbi.nlm.nih.gov/pubmed/36371529
http://dx.doi.org/10.1038/s41598-022-23906-2
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author Sekhar, Konjeti R.
Hanna, David N.
Cyr, Sriram
Baechle, Jordan J.
Kuravi, Sudhakiranmayi
Balusu, Ramesh
Rathmell, Kimryn
Baregamian, Naira
author_facet Sekhar, Konjeti R.
Hanna, David N.
Cyr, Sriram
Baechle, Jordan J.
Kuravi, Sudhakiranmayi
Balusu, Ramesh
Rathmell, Kimryn
Baregamian, Naira
author_sort Sekhar, Konjeti R.
collection PubMed
description Papillary thyroid carcinoma (PTC) demonstrates significantly reduced patient survival with metastatic progression. Tumor progression can be influenced by metabolism, including antioxidant glutathione (GSH). Glutathione peroxidase 4 (GPX4) is a selenoenzyme that uses GSH as a co-factor to regulate lipid peroxidation of cell membranes during increased oxidative stress. GPX4 suppression in tumor cells can induce ferroptosis. This study aims to examine ferroptosis as a potentially critical pathway in effective targeting of thyroid cancer (TC) cells. We treated human TC cells (K1, MDA-T68, MDA-T32, TPC1) with (1S,3R)-RSL3 (RSL3), a small-molecule inhibitor of GPX4 and examined the effects on ferroptosis, tumor cell survival and migration, spheroid formation, oxidative stress, DNA damage repair response, and mTOR signaling pathway in vitro. GPX4 inhibition activated ferroptosis, inducing TC cell death, rapid rise in reactive oxygen species and effectively arrested cell migration in vitro. Suppression of mTOR signaling pathway triggered autophagy. GPX4 genetic knockdown mirrored RSL3 effect on mTOR pathway suppression. RSL3 subdued DNA damage repair response by suppressing phosphorylation of nucleophosmin 1 (NPM1). Thus, observed potent induction of ferroptosis, GPX4-dependent novel suppression of mTOR pathway and DNA damage repair response in preclinical in vitro model of TC supports GPX4 targeting for therapeutic benefit in advanced therapy-resistant thyroid cancers.
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spelling pubmed-96534792022-11-15 Glutathione peroxidase 4 inhibition induces ferroptosis and mTOR pathway suppression in thyroid cancer Sekhar, Konjeti R. Hanna, David N. Cyr, Sriram Baechle, Jordan J. Kuravi, Sudhakiranmayi Balusu, Ramesh Rathmell, Kimryn Baregamian, Naira Sci Rep Article Papillary thyroid carcinoma (PTC) demonstrates significantly reduced patient survival with metastatic progression. Tumor progression can be influenced by metabolism, including antioxidant glutathione (GSH). Glutathione peroxidase 4 (GPX4) is a selenoenzyme that uses GSH as a co-factor to regulate lipid peroxidation of cell membranes during increased oxidative stress. GPX4 suppression in tumor cells can induce ferroptosis. This study aims to examine ferroptosis as a potentially critical pathway in effective targeting of thyroid cancer (TC) cells. We treated human TC cells (K1, MDA-T68, MDA-T32, TPC1) with (1S,3R)-RSL3 (RSL3), a small-molecule inhibitor of GPX4 and examined the effects on ferroptosis, tumor cell survival and migration, spheroid formation, oxidative stress, DNA damage repair response, and mTOR signaling pathway in vitro. GPX4 inhibition activated ferroptosis, inducing TC cell death, rapid rise in reactive oxygen species and effectively arrested cell migration in vitro. Suppression of mTOR signaling pathway triggered autophagy. GPX4 genetic knockdown mirrored RSL3 effect on mTOR pathway suppression. RSL3 subdued DNA damage repair response by suppressing phosphorylation of nucleophosmin 1 (NPM1). Thus, observed potent induction of ferroptosis, GPX4-dependent novel suppression of mTOR pathway and DNA damage repair response in preclinical in vitro model of TC supports GPX4 targeting for therapeutic benefit in advanced therapy-resistant thyroid cancers. Nature Publishing Group UK 2022-11-12 /pmc/articles/PMC9653479/ /pubmed/36371529 http://dx.doi.org/10.1038/s41598-022-23906-2 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sekhar, Konjeti R.
Hanna, David N.
Cyr, Sriram
Baechle, Jordan J.
Kuravi, Sudhakiranmayi
Balusu, Ramesh
Rathmell, Kimryn
Baregamian, Naira
Glutathione peroxidase 4 inhibition induces ferroptosis and mTOR pathway suppression in thyroid cancer
title Glutathione peroxidase 4 inhibition induces ferroptosis and mTOR pathway suppression in thyroid cancer
title_full Glutathione peroxidase 4 inhibition induces ferroptosis and mTOR pathway suppression in thyroid cancer
title_fullStr Glutathione peroxidase 4 inhibition induces ferroptosis and mTOR pathway suppression in thyroid cancer
title_full_unstemmed Glutathione peroxidase 4 inhibition induces ferroptosis and mTOR pathway suppression in thyroid cancer
title_short Glutathione peroxidase 4 inhibition induces ferroptosis and mTOR pathway suppression in thyroid cancer
title_sort glutathione peroxidase 4 inhibition induces ferroptosis and mtor pathway suppression in thyroid cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9653479/
https://www.ncbi.nlm.nih.gov/pubmed/36371529
http://dx.doi.org/10.1038/s41598-022-23906-2
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