Cargando…
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...
Autores principales: | , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784638455784931328 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8783118 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT lvchao narciclasinetargetsstat3viadistinctmechanismsintamoxifenresistantbreastcancercells AT huangyun narciclasinetargetsstat3viadistinctmechanismsintamoxifenresistantbreastcancercells AT huangrui narciclasinetargetsstat3viadistinctmechanismsintamoxifenresistantbreastcancercells AT wangqun narciclasinetargetsstat3viadistinctmechanismsintamoxifenresistantbreastcancercells AT zhanghongwei narciclasinetargetsstat3viadistinctmechanismsintamoxifenresistantbreastcancercells AT jinjinmei narciclasinetargetsstat3viadistinctmechanismsintamoxifenresistantbreastcancercells AT ludong narciclasinetargetsstat3viadistinctmechanismsintamoxifenresistantbreastcancercells AT zhouyudong narciclasinetargetsstat3viadistinctmechanismsintamoxifenresistantbreastcancercells AT shenyunheng narciclasinetargetsstat3viadistinctmechanismsintamoxifenresistantbreastcancercells AT zhangweidong narciclasinetargetsstat3viadistinctmechanismsintamoxifenresistantbreastcancercells AT luanxin narciclasinetargetsstat3viadistinctmechanismsintamoxifenresistantbreastcancercells AT liusanhong narciclasinetargetsstat3viadistinctmechanismsintamoxifenresistantbreastcancercells |