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The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells
STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented. In this report, we performed h...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995615/ https://www.ncbi.nlm.nih.gov/pubmed/31847229 http://dx.doi.org/10.3390/biom9120875 |
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author | Lee, Jong Hyun Mohan, Chakrabhavi Dhananjaya Basappa, Salundi Rangappa, Shobith Chinnathambi, Arunachalam Alahmadi, Tahani Awad Alharbi, Sulaiman Ali Kumar, Alan Prem Sethi, Gautam Ahn, Kwang Seok Rangappa, Kanchugarakoppal S |
author_facet | Lee, Jong Hyun Mohan, Chakrabhavi Dhananjaya Basappa, Salundi Rangappa, Shobith Chinnathambi, Arunachalam Alahmadi, Tahani Awad Alharbi, Sulaiman Ali Kumar, Alan Prem Sethi, Gautam Ahn, Kwang Seok Rangappa, Kanchugarakoppal S |
author_sort | Lee, Jong Hyun |
collection | PubMed |
description | STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented. In this report, we performed high-throughput virtual screening in search of STAT3 signaling inhibitors using a cheminformatics platform and identified 2-Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) as the inhibitor of the STAT3 signaling pathway. The predicted hit was evaluated in non-small cell lung cancer (NSCLC) cell lines for its STAT3 inhibitory activity. In vitro experiments suggested that ACHP decreased the cell viability and inhibited the phosphorylation of STAT3 on Tyr705 of NSCLC cells. In addition, ACHP imparted inhibitory activity on the constitutive activation of upstream protein tyrosine kinases, including JAK1, JAK2, and Src. ACHP decreased the nuclear translocation of STAT3 and downregulated its DNA binding ability. Apoptosis was evidenced by cleavage of caspase-3 and PARP with the subsequent decline in antiapoptotic proteins, including Bcl-2, Bcl-xl, and survivin. Overall, we report that ACHP can act as a potent STAT3 signaling inhibitor in NSCLC cell lines. |
format | Online Article Text |
id | pubmed-6995615 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-69956152020-02-13 The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells Lee, Jong Hyun Mohan, Chakrabhavi Dhananjaya Basappa, Salundi Rangappa, Shobith Chinnathambi, Arunachalam Alahmadi, Tahani Awad Alharbi, Sulaiman Ali Kumar, Alan Prem Sethi, Gautam Ahn, Kwang Seok Rangappa, Kanchugarakoppal S Biomolecules Article STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented. In this report, we performed high-throughput virtual screening in search of STAT3 signaling inhibitors using a cheminformatics platform and identified 2-Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) as the inhibitor of the STAT3 signaling pathway. The predicted hit was evaluated in non-small cell lung cancer (NSCLC) cell lines for its STAT3 inhibitory activity. In vitro experiments suggested that ACHP decreased the cell viability and inhibited the phosphorylation of STAT3 on Tyr705 of NSCLC cells. In addition, ACHP imparted inhibitory activity on the constitutive activation of upstream protein tyrosine kinases, including JAK1, JAK2, and Src. ACHP decreased the nuclear translocation of STAT3 and downregulated its DNA binding ability. Apoptosis was evidenced by cleavage of caspase-3 and PARP with the subsequent decline in antiapoptotic proteins, including Bcl-2, Bcl-xl, and survivin. Overall, we report that ACHP can act as a potent STAT3 signaling inhibitor in NSCLC cell lines. MDPI 2019-12-13 /pmc/articles/PMC6995615/ /pubmed/31847229 http://dx.doi.org/10.3390/biom9120875 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Lee, Jong Hyun Mohan, Chakrabhavi Dhananjaya Basappa, Salundi Rangappa, Shobith Chinnathambi, Arunachalam Alahmadi, Tahani Awad Alharbi, Sulaiman Ali Kumar, Alan Prem Sethi, Gautam Ahn, Kwang Seok Rangappa, Kanchugarakoppal S The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells |
title | The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells |
title_full | The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells |
title_fullStr | The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells |
title_full_unstemmed | The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells |
title_short | The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells |
title_sort | iκb kinase inhibitor achp targets the stat3 signaling pathway in human non-small cell lung carcinoma cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995615/ https://www.ncbi.nlm.nih.gov/pubmed/31847229 http://dx.doi.org/10.3390/biom9120875 |
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