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
Abstract
Abstract
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-TXA2 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.
Funder
National Natural Science Foundation of China
Health and Family Planning Commission of Hubei Province
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology
Cited by
27 articles.
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