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Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells

MET overactivation is one of the crucial reasons for tyrosine kinase inhibitor (TKI) resistance, but the mechanisms are not wholly clear. Here, COX2, TOPK, and MET expression were examined in EGFR-activating mutated NSCLC by immunohistochemical (IHC) analysis. The relationship between COX2, TOPK, an...

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Autores principales: Xiao, Juanjuan, Wang, Fei, Lu, Hui, Xu, Sanpeng, Zou, Ling, Tian, Qin, Fu, Yang, Lin, Xuan, Liu, Lin, Yuan, Ping, Ni, Xiaofang, Ma, Tengfei, Zeng, Fanfan, Xue, Peipei, Xiu, Ruijuan, Zhang, Jianmin, Ji, Xinying, Hu, Hongbo, Lu, Shangyun, Dai, Hongtian, Li, Yuan, Chu, Qian, Zhao, Xia, Duan, Qiuhong, Zhu, Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791885/
https://www.ncbi.nlm.nih.gov/pubmed/31611604
http://dx.doi.org/10.1038/s41419-019-2020-4
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author Xiao, Juanjuan
Wang, Fei
Lu, Hui
Xu, Sanpeng
Zou, Ling
Tian, Qin
Fu, Yang
Lin, Xuan
Liu, Lin
Yuan, Ping
Ni, Xiaofang
Ma, Tengfei
Zeng, Fanfan
Xue, Peipei
Xiu, Ruijuan
Zhang, Jianmin
Ji, Xinying
Hu, Hongbo
Lu, Shangyun
Dai, Hongtian
Li, Yuan
Chu, Qian
Zhao, Xia
Duan, Qiuhong
Zhu, Feng
author_facet Xiao, Juanjuan
Wang, Fei
Lu, Hui
Xu, Sanpeng
Zou, Ling
Tian, Qin
Fu, Yang
Lin, Xuan
Liu, Lin
Yuan, Ping
Ni, Xiaofang
Ma, Tengfei
Zeng, Fanfan
Xue, Peipei
Xiu, Ruijuan
Zhang, Jianmin
Ji, Xinying
Hu, Hongbo
Lu, Shangyun
Dai, Hongtian
Li, Yuan
Chu, Qian
Zhao, Xia
Duan, Qiuhong
Zhu, Feng
author_sort Xiao, Juanjuan
collection PubMed
description MET overactivation is one of the crucial reasons for tyrosine kinase inhibitor (TKI) resistance, but the mechanisms are not wholly clear. Here, COX2, TOPK, and MET expression were examined in EGFR-activating mutated NSCLC by immunohistochemical (IHC) analysis. The relationship between COX2, TOPK, and MET was explored in vitro and ex vivo. In addition, the inhibition of HCC827GR cell growth by combining COX2 inhibitor (celecoxib), TOPK inhibitor (pantoprazole), and gefitinib was verified ex vivo and in vivo. We found that COX2 and TOPK were highly expressed in EGFR-activating mutated NSCLC and the progression-free survival (PFS) of triple-positive (COX2, MET, and TOPK) patients was shorter than that of triple-negative patients. Then, we observed that the COX2-TXA(2) signaling pathway modulated MET through AP-1, resulting in an inhibition of apoptosis in gefitinib-resistant cells. Moreover, we demonstrated that MET could phosphorylate TOPK at Tyr74 and then prevent apoptosis in gefitinib-resistant cells. In line with these findings, the combination of celecoxib, pantoprazole, and gefitinib could induce apoptosis in gefitinib-resistant cells and inhibit tumor growth ex vivo and in vivo. Our work reveals a novel COX2/MET/TOPK signaling axis that can prevent apoptosis in gefitinib-resistant cells and suggests that a triple combination of FDA-approved drugs would provide a low-cost and practical strategy to overcome gefitinib resistance.
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spelling pubmed-67918852019-10-15 Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells Xiao, Juanjuan Wang, Fei Lu, Hui Xu, Sanpeng Zou, Ling Tian, Qin Fu, Yang Lin, Xuan Liu, Lin Yuan, Ping Ni, Xiaofang Ma, Tengfei Zeng, Fanfan Xue, Peipei Xiu, Ruijuan Zhang, Jianmin Ji, Xinying Hu, Hongbo Lu, Shangyun Dai, Hongtian Li, Yuan Chu, Qian Zhao, Xia Duan, Qiuhong Zhu, Feng Cell Death Dis Article MET overactivation is one of the crucial reasons for tyrosine kinase inhibitor (TKI) resistance, but the mechanisms are not wholly clear. Here, COX2, TOPK, and MET expression were examined in EGFR-activating mutated NSCLC by immunohistochemical (IHC) analysis. The relationship between COX2, TOPK, and MET was explored in vitro and ex vivo. In addition, the inhibition of HCC827GR cell growth by combining COX2 inhibitor (celecoxib), TOPK inhibitor (pantoprazole), and gefitinib was verified ex vivo and in vivo. We found that COX2 and TOPK were highly expressed in EGFR-activating mutated NSCLC and the progression-free survival (PFS) of triple-positive (COX2, MET, and TOPK) patients was shorter than that of triple-negative patients. Then, we observed that the COX2-TXA(2) signaling pathway modulated MET through AP-1, resulting in an inhibition of apoptosis in gefitinib-resistant cells. Moreover, we demonstrated that MET could phosphorylate TOPK at Tyr74 and then prevent apoptosis in gefitinib-resistant cells. In line with these findings, the combination of celecoxib, pantoprazole, and gefitinib could induce apoptosis in gefitinib-resistant cells and inhibit tumor growth ex vivo and in vivo. Our work reveals a novel COX2/MET/TOPK signaling axis that can prevent apoptosis in gefitinib-resistant cells and suggests that a triple combination of FDA-approved drugs would provide a low-cost and practical strategy to overcome gefitinib resistance. Nature Publishing Group UK 2019-10-14 /pmc/articles/PMC6791885/ /pubmed/31611604 http://dx.doi.org/10.1038/s41419-019-2020-4 Text en © The Author(s) 2019 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
Xiao, Juanjuan
Wang, Fei
Lu, Hui
Xu, Sanpeng
Zou, Ling
Tian, Qin
Fu, Yang
Lin, Xuan
Liu, Lin
Yuan, Ping
Ni, Xiaofang
Ma, Tengfei
Zeng, Fanfan
Xue, Peipei
Xiu, Ruijuan
Zhang, Jianmin
Ji, Xinying
Hu, Hongbo
Lu, Shangyun
Dai, Hongtian
Li, Yuan
Chu, Qian
Zhao, Xia
Duan, Qiuhong
Zhu, Feng
Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells
title Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells
title_full Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells
title_fullStr Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells
title_full_unstemmed Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells
title_short Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells
title_sort targeting the cox2/met/topk signaling axis induces apoptosis in gefitinib-resistant nsclc cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791885/
https://www.ncbi.nlm.nih.gov/pubmed/31611604
http://dx.doi.org/10.1038/s41419-019-2020-4
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