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SHARPIN Enhances Ferroptosis in Synovial Sarcoma Cells via NF-κB- and PRMT5-Mediated PGC1α Reduction

SIMPLE SUMMARY: Sarcoma is difficult to treat because of its rarity. Ferroptosis is a new type of cell death mediated by ferrous iron. In the present study, we aimed to clarify the effect of ferroptosis in sarcoma. As compared with noncancer and carcinoma cell lines, ferroptosis is more sensitive in...

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Autores principales: Tamiya, Hironari, Urushihara, Naoko, Shizuma, Kazuko, Ogawa, Hisataka, Nakai, Sho, Wakamatsu, Toru, Takenaka, Satoshi, Kakunaga, Shigeki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10341212/
https://www.ncbi.nlm.nih.gov/pubmed/37444594
http://dx.doi.org/10.3390/cancers15133484
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author Tamiya, Hironari
Urushihara, Naoko
Shizuma, Kazuko
Ogawa, Hisataka
Nakai, Sho
Wakamatsu, Toru
Takenaka, Satoshi
Kakunaga, Shigeki
author_facet Tamiya, Hironari
Urushihara, Naoko
Shizuma, Kazuko
Ogawa, Hisataka
Nakai, Sho
Wakamatsu, Toru
Takenaka, Satoshi
Kakunaga, Shigeki
author_sort Tamiya, Hironari
collection PubMed
description SIMPLE SUMMARY: Sarcoma is difficult to treat because of its rarity. Ferroptosis is a new type of cell death mediated by ferrous iron. In the present study, we aimed to clarify the effect of ferroptosis in sarcoma. As compared with noncancer and carcinoma cell lines, ferroptosis is more sensitive in most of the sarcoma cell lines. Moreover, transferrin receptor 1 (TFRC) and SHANK-associated RH domain interactor (SHARPIN), both of which are oncogenic factors and related to poor overall survival, are highly expressed, particularly in synovial sarcoma cell lines. Furthermore, we discovered that SHARPIN is a positive regulator of ferroptosis through nuclear factor-kappa B (NF-κΒ) and protein arginine methyltransferase 5 (PRMT5)-mediated PGC1α reduction. In summary, we suggest that ferroptosis could be a therapeutic target in sarcoma, particularly in subpopulations with high TFRC and SHARPIN expression. ABSTRACT: Sarcoma is a rare type of cancer for which new therapeutic agents are required. Ferroptosis is a nonapoptotic cell death triggered by iron-mediated lipid peroxidation. We found that TFRC, an iron uptake protein, was expressed at higher levels in sarcoma cell lines than in noncancer and carcinoma cell lines. Glutathione peroxidase 4 (GPX4) protects cells against ferroptosis, and its inhibition using RAS-selective lethal 3 (RSL3) had an antitumor effect that was more pronounced in sarcoma cell lines, particularly synovial sarcoma cells, compared to non-sarcoma cells. Because NF-κB can provoke ferroptosis, we examined the role of SHARPIN, an activator of NF-κB, in sarcoma. We found that SHARPIN expression was significantly associated with reduced survival in cohorts of patients with cancer, including sarcoma. In addition, SHARPIN promoted the sensitivity of sarcoma cells to ferroptosis. Further analyses revealed that the PGC1α/NRF2/SLC7A11 axis and BNIP3L/NIX-mediated mitophagy are regulated through NF-κB and PRMT5 downstream of SHARPIN. Our findings suggest that ferroptosis could have a therapeutic effect in sarcoma, particularly in subpopulations with high TFRC and SHARPIN expression.
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spelling pubmed-103412122023-07-14 SHARPIN Enhances Ferroptosis in Synovial Sarcoma Cells via NF-κB- and PRMT5-Mediated PGC1α Reduction Tamiya, Hironari Urushihara, Naoko Shizuma, Kazuko Ogawa, Hisataka Nakai, Sho Wakamatsu, Toru Takenaka, Satoshi Kakunaga, Shigeki Cancers (Basel) Article SIMPLE SUMMARY: Sarcoma is difficult to treat because of its rarity. Ferroptosis is a new type of cell death mediated by ferrous iron. In the present study, we aimed to clarify the effect of ferroptosis in sarcoma. As compared with noncancer and carcinoma cell lines, ferroptosis is more sensitive in most of the sarcoma cell lines. Moreover, transferrin receptor 1 (TFRC) and SHANK-associated RH domain interactor (SHARPIN), both of which are oncogenic factors and related to poor overall survival, are highly expressed, particularly in synovial sarcoma cell lines. Furthermore, we discovered that SHARPIN is a positive regulator of ferroptosis through nuclear factor-kappa B (NF-κΒ) and protein arginine methyltransferase 5 (PRMT5)-mediated PGC1α reduction. In summary, we suggest that ferroptosis could be a therapeutic target in sarcoma, particularly in subpopulations with high TFRC and SHARPIN expression. ABSTRACT: Sarcoma is a rare type of cancer for which new therapeutic agents are required. Ferroptosis is a nonapoptotic cell death triggered by iron-mediated lipid peroxidation. We found that TFRC, an iron uptake protein, was expressed at higher levels in sarcoma cell lines than in noncancer and carcinoma cell lines. Glutathione peroxidase 4 (GPX4) protects cells against ferroptosis, and its inhibition using RAS-selective lethal 3 (RSL3) had an antitumor effect that was more pronounced in sarcoma cell lines, particularly synovial sarcoma cells, compared to non-sarcoma cells. Because NF-κB can provoke ferroptosis, we examined the role of SHARPIN, an activator of NF-κB, in sarcoma. We found that SHARPIN expression was significantly associated with reduced survival in cohorts of patients with cancer, including sarcoma. In addition, SHARPIN promoted the sensitivity of sarcoma cells to ferroptosis. Further analyses revealed that the PGC1α/NRF2/SLC7A11 axis and BNIP3L/NIX-mediated mitophagy are regulated through NF-κB and PRMT5 downstream of SHARPIN. Our findings suggest that ferroptosis could have a therapeutic effect in sarcoma, particularly in subpopulations with high TFRC and SHARPIN expression. MDPI 2023-07-04 /pmc/articles/PMC10341212/ /pubmed/37444594 http://dx.doi.org/10.3390/cancers15133484 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tamiya, Hironari
Urushihara, Naoko
Shizuma, Kazuko
Ogawa, Hisataka
Nakai, Sho
Wakamatsu, Toru
Takenaka, Satoshi
Kakunaga, Shigeki
SHARPIN Enhances Ferroptosis in Synovial Sarcoma Cells via NF-κB- and PRMT5-Mediated PGC1α Reduction
title SHARPIN Enhances Ferroptosis in Synovial Sarcoma Cells via NF-κB- and PRMT5-Mediated PGC1α Reduction
title_full SHARPIN Enhances Ferroptosis in Synovial Sarcoma Cells via NF-κB- and PRMT5-Mediated PGC1α Reduction
title_fullStr SHARPIN Enhances Ferroptosis in Synovial Sarcoma Cells via NF-κB- and PRMT5-Mediated PGC1α Reduction
title_full_unstemmed SHARPIN Enhances Ferroptosis in Synovial Sarcoma Cells via NF-κB- and PRMT5-Mediated PGC1α Reduction
title_short SHARPIN Enhances Ferroptosis in Synovial Sarcoma Cells via NF-κB- and PRMT5-Mediated PGC1α Reduction
title_sort sharpin enhances ferroptosis in synovial sarcoma cells via nf-κb- and prmt5-mediated pgc1α reduction
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10341212/
https://www.ncbi.nlm.nih.gov/pubmed/37444594
http://dx.doi.org/10.3390/cancers15133484
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