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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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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. |
format | Online Article Text |
id | pubmed-7906907 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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