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Narciclasine targets STAT3 via distinct mechanisms in tamoxifen-resistant breast cancer cells

STAT3 is constitutively activated in multiple malignant tumors. Compared with regular estrogen receptor (ER)-positive breast cancers, the patients with tamoxifen-resistant breast cancers often exhibit higher levels of STAT3 phosphorylation. Narciclasine (Nar) possesses strong inhibiting effects agai...

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Autores principales: Lv, Chao, Huang, Yun, Huang, Rui, Wang, Qun, Zhang, Hongwei, Jin, Jinmei, Lu, Dong, Zhou, Yudong, Shen, Yunheng, Zhang, Weidong, Luan, Xin, Liu, Sanhong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783118/
https://www.ncbi.nlm.nih.gov/pubmed/35118192
http://dx.doi.org/10.1016/j.omto.2021.12.025
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author Lv, Chao
Huang, Yun
Huang, Rui
Wang, Qun
Zhang, Hongwei
Jin, Jinmei
Lu, Dong
Zhou, Yudong
Shen, Yunheng
Zhang, Weidong
Luan, Xin
Liu, Sanhong
author_facet Lv, Chao
Huang, Yun
Huang, Rui
Wang, Qun
Zhang, Hongwei
Jin, Jinmei
Lu, Dong
Zhou, Yudong
Shen, Yunheng
Zhang, Weidong
Luan, Xin
Liu, Sanhong
author_sort Lv, Chao
collection PubMed
description STAT3 is constitutively activated in multiple malignant tumors. Compared with regular estrogen receptor (ER)-positive breast cancers, the patients with tamoxifen-resistant breast cancers often exhibit higher levels of STAT3 phosphorylation. Narciclasine (Nar) possesses strong inhibiting effects against a variety of cancer cells; however, the underlying antitumor target(s)/mechanism(s) remains barely understood. In this study, we successfully identified the STAT3 was the direct target of Nar through the combination strategies of connectivity map and drug affinity responsive target stability. In MCF7 cells, Nar could suppress phosphorylation, activation, dimerization, and nuclear translocation of STAT3 by directly binding with the STAT3 SH2 domain. In addition, Nar could specifically degrade total STAT3 via the proteasome pathway in MCF-7/TR (tamoxifen-resistant MCF-7) cells. This distinct mechanism of Nar-targeting STAT3 was mainly attributed to the various levels of reactive oxygen species in regular and tamoxifen-resistant ER-positive breast cancer cells. Meanwhile, Nar-loaded nanoparticles could markedly decrease the protein levels of STAT3 in tumors, resulting in significantly increased MCF-7/TR xenograft tumor regression without obvious toxicity. Our findings successfully highlight the STAT3 as the direct therapeutic target of Nar in ER-positive breast cancer cells, especially, Nar leaded STAT3 degradation as a promising strategy for the tamoxifen-resistant breast cancer treatment.
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spelling pubmed-87831182022-02-02 Narciclasine targets STAT3 via distinct mechanisms in tamoxifen-resistant breast cancer cells Lv, Chao Huang, Yun Huang, Rui Wang, Qun Zhang, Hongwei Jin, Jinmei Lu, Dong Zhou, Yudong Shen, Yunheng Zhang, Weidong Luan, Xin Liu, Sanhong Mol Ther Oncolytics Original Article STAT3 is constitutively activated in multiple malignant tumors. Compared with regular estrogen receptor (ER)-positive breast cancers, the patients with tamoxifen-resistant breast cancers often exhibit higher levels of STAT3 phosphorylation. Narciclasine (Nar) possesses strong inhibiting effects against a variety of cancer cells; however, the underlying antitumor target(s)/mechanism(s) remains barely understood. In this study, we successfully identified the STAT3 was the direct target of Nar through the combination strategies of connectivity map and drug affinity responsive target stability. In MCF7 cells, Nar could suppress phosphorylation, activation, dimerization, and nuclear translocation of STAT3 by directly binding with the STAT3 SH2 domain. In addition, Nar could specifically degrade total STAT3 via the proteasome pathway in MCF-7/TR (tamoxifen-resistant MCF-7) cells. This distinct mechanism of Nar-targeting STAT3 was mainly attributed to the various levels of reactive oxygen species in regular and tamoxifen-resistant ER-positive breast cancer cells. Meanwhile, Nar-loaded nanoparticles could markedly decrease the protein levels of STAT3 in tumors, resulting in significantly increased MCF-7/TR xenograft tumor regression without obvious toxicity. Our findings successfully highlight the STAT3 as the direct therapeutic target of Nar in ER-positive breast cancer cells, especially, Nar leaded STAT3 degradation as a promising strategy for the tamoxifen-resistant breast cancer treatment. American Society of Gene & Cell Therapy 2022-01-03 /pmc/articles/PMC8783118/ /pubmed/35118192 http://dx.doi.org/10.1016/j.omto.2021.12.025 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Lv, Chao
Huang, Yun
Huang, Rui
Wang, Qun
Zhang, Hongwei
Jin, Jinmei
Lu, Dong
Zhou, Yudong
Shen, Yunheng
Zhang, Weidong
Luan, Xin
Liu, Sanhong
Narciclasine targets STAT3 via distinct mechanisms in tamoxifen-resistant breast cancer cells
title Narciclasine targets STAT3 via distinct mechanisms in tamoxifen-resistant breast cancer cells
title_full Narciclasine targets STAT3 via distinct mechanisms in tamoxifen-resistant breast cancer cells
title_fullStr Narciclasine targets STAT3 via distinct mechanisms in tamoxifen-resistant breast cancer cells
title_full_unstemmed Narciclasine targets STAT3 via distinct mechanisms in tamoxifen-resistant breast cancer cells
title_short Narciclasine targets STAT3 via distinct mechanisms in tamoxifen-resistant breast cancer cells
title_sort narciclasine targets stat3 via distinct mechanisms in tamoxifen-resistant breast cancer cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8783118/
https://www.ncbi.nlm.nih.gov/pubmed/35118192
http://dx.doi.org/10.1016/j.omto.2021.12.025
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