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Targeting STAT3 by a small molecule suppresses pancreatic cancer progression

Pancreatic cancer is lethal in over 90% of cases since it is resistant to current therapeutic strategies. The key role of STAT3 in promoting pancreatic cancer progression has been proven, but effective interventions that suppress STAT3 activities are limited. The development of novel anticancer agen...

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Autores principales: Chen, Huang, Bian, Aiwu, Yang, Lian-fang, Yin, Xuan, Wang, Jie, Ti, Chaowen, Miao, Ying, Peng, Shihong, Xu, Shifen, Liu, Mingyao, Qiu, Wen-Wei, Yi, Zhengfang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906907/
https://www.ncbi.nlm.nih.gov/pubmed/33420372
http://dx.doi.org/10.1038/s41388-020-01626-z
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author Chen, Huang
Bian, Aiwu
Yang, Lian-fang
Yin, Xuan
Wang, Jie
Ti, Chaowen
Miao, Ying
Peng, Shihong
Xu, Shifen
Liu, Mingyao
Qiu, Wen-Wei
Yi, Zhengfang
author_facet Chen, Huang
Bian, Aiwu
Yang, Lian-fang
Yin, Xuan
Wang, Jie
Ti, Chaowen
Miao, Ying
Peng, Shihong
Xu, Shifen
Liu, Mingyao
Qiu, Wen-Wei
Yi, Zhengfang
author_sort Chen, Huang
collection PubMed
description Pancreatic cancer is lethal in over 90% of cases since it is resistant to current therapeutic strategies. The key role of STAT3 in promoting pancreatic cancer progression has been proven, but effective interventions that suppress STAT3 activities are limited. The development of novel anticancer agents that directly target STAT3 may have potential clinical benefits for pancreatic cancer treatment. Here, we report a new small-molecule inhibitor (N4) with potent antitumor bioactivity, which inhibits multiple oncogenic processes in pancreatic cancer. N4 blocked STAT3 and phospho-tyrosine (pTyr) peptide interactions in fluorescence polarization (FP) assay, specifically abolished phosphor-STAT3 (Tyr705), and suppressed expression of STAT3 downstream genes. The mechanism involved the direct binding of N4 to the STAT3 SH2 domain, thereby, the STAT3 dimerization, STAT3-EGFR, and STAT3-NF-κB cross-talk were efficiently inhibited. In animal models of pancreatic cancer, N4 was well tolerated, suppressed tumor growth and metastasis, and significantly prolonged survival of tumor-bearing mice. Our results offer a preclinical proof of concept for N4 as a candidate therapeutic compound for pancreatic cancer.
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spelling pubmed-79069072021-03-09 Targeting STAT3 by a small molecule suppresses pancreatic cancer progression Chen, Huang Bian, Aiwu Yang, Lian-fang Yin, Xuan Wang, Jie Ti, Chaowen Miao, Ying Peng, Shihong Xu, Shifen Liu, Mingyao Qiu, Wen-Wei Yi, Zhengfang Oncogene Article Pancreatic cancer is lethal in over 90% of cases since it is resistant to current therapeutic strategies. The key role of STAT3 in promoting pancreatic cancer progression has been proven, but effective interventions that suppress STAT3 activities are limited. The development of novel anticancer agents that directly target STAT3 may have potential clinical benefits for pancreatic cancer treatment. Here, we report a new small-molecule inhibitor (N4) with potent antitumor bioactivity, which inhibits multiple oncogenic processes in pancreatic cancer. N4 blocked STAT3 and phospho-tyrosine (pTyr) peptide interactions in fluorescence polarization (FP) assay, specifically abolished phosphor-STAT3 (Tyr705), and suppressed expression of STAT3 downstream genes. The mechanism involved the direct binding of N4 to the STAT3 SH2 domain, thereby, the STAT3 dimerization, STAT3-EGFR, and STAT3-NF-κB cross-talk were efficiently inhibited. In animal models of pancreatic cancer, N4 was well tolerated, suppressed tumor growth and metastasis, and significantly prolonged survival of tumor-bearing mice. Our results offer a preclinical proof of concept for N4 as a candidate therapeutic compound for pancreatic cancer. Nature Publishing Group UK 2021-01-08 2021 /pmc/articles/PMC7906907/ /pubmed/33420372 http://dx.doi.org/10.1038/s41388-020-01626-z Text en © The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature 2021 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chen, Huang
Bian, Aiwu
Yang, Lian-fang
Yin, Xuan
Wang, Jie
Ti, Chaowen
Miao, Ying
Peng, Shihong
Xu, Shifen
Liu, Mingyao
Qiu, Wen-Wei
Yi, Zhengfang
Targeting STAT3 by a small molecule suppresses pancreatic cancer progression
title Targeting STAT3 by a small molecule suppresses pancreatic cancer progression
title_full Targeting STAT3 by a small molecule suppresses pancreatic cancer progression
title_fullStr Targeting STAT3 by a small molecule suppresses pancreatic cancer progression
title_full_unstemmed Targeting STAT3 by a small molecule suppresses pancreatic cancer progression
title_short Targeting STAT3 by a small molecule suppresses pancreatic cancer progression
title_sort targeting stat3 by a small molecule suppresses pancreatic cancer progression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906907/
https://www.ncbi.nlm.nih.gov/pubmed/33420372
http://dx.doi.org/10.1038/s41388-020-01626-z
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