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J Cancer Res Clin Oncol. 2019 Apr;145(4):861-872. doi: 10.1007/s00432-019-02845-y. Epub 2019 Jan 19.

GLRX inhibition enhances the effects of geftinib in EGFR-TKI-resistant NSCLC cells through FoxM1 signaling pathway.

Wang L1,2, Liu J3, Liu J1, Chen X1,2, Chang M1,2, Li J1,2, Zhou J4,5, Bai C6,7, Song Y8,9.

Author information

1
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China.
2
Shanghai Respiratory Research Institute, Shanghai, China.
3
Department of Pathology, The Affiliated Yantai Yuhuangding Hospital, Qingdao University, Yantai, China.
4
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China. zhou.jian@fudan.edu.cn.
5
Shanghai Respiratory Research Institute, Shanghai, China. zhou.jian@fudan.edu.cn.
6
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China. bai.chunxue@zs-hospital.sh.cn.
7
Shanghai Respiratory Research Institute, Shanghai, China. bai.chunxue@zs-hospital.sh.cn.
8
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Rd, Shanghai, 200032, China. song.yuanlin@zs-hospital.sh.cn.
9
Shanghai Respiratory Research Institute, Shanghai, China. song.yuanlin@zs-hospital.sh.cn.

Abstract

PURPOSE:

Non-small-cell lung cancer (NSCLC) is the most common form of lung cancer. Gefitinib is one of the most accepted therapies against NSCLC in those carrying EGFR mutations, but it is only effective in approximately 20% of patients with NSCLC. Thus, alternative therapeutic interventions are urgently needed to overcome gefitinib resistance. Glutaredoxin (GLRX) plays a key role in oxidative stress. However, whether GLRX inhibition could enhance gefitinib efficacy in the gefitinib-resistant NSCLC cells is unknown. In this study, we aimed to determine whether combined inhibition of GLRX could enhance growth-inhibitory effects of gefitinib in gefitinib-resistant NSCLC cells.

METHODS:

Real-time PCR and western blotting were used to examine the mRNA and protein levels of GLRX in gefitinib-sensitive PC9 and HCC827 and -resistant human lung adenocarcinoma PC9R, HCC827R, and H1975 cells. Cell Counting Kit-8, flow cytometry, JC-1 staining, and reactive oxygen species (ROS) assays were used to evaluate cell proliferation, cell cycle progression, mitochondrial membrane potential, and ROS generation, respectively. Mouse tumor xenografts were used to assess the effect of GLRX in vivo.

RESULTS:

We found that GLRX was upregulated in gefitinib-resistant PC9R, HCC827R, and H1975 cells. GLRX inhibition enhanced the effects of geftinib in gefitinib-resistant cell proliferation in vitro and in vivo and promoted apoptosis and cell cycle arrest via the EGFR/Forkhead Box M1 (FoxM1) signaling pathway, indicating that combined inhibition of GLRX could enhance growth-inhibitory effects of gefitinib in gefitinib-resistant NSCLC cells.

CONCLUSIONS:

Our results suggest that GLRX inhibition enhances the effects of geftinib in EGFR-TKI-resistant NSCLC cells. Thus, GLRX may represent a therapeutic target for increasing the efficiency of gefitinib treatment.

KEYWORDS:

Drug resistance; FoxM1; GLRX; Gefitinib; Non-small-cell lung cancer

PMID:
30661098
DOI:
10.1007/s00432-019-02845-y
[Indexed for MEDLINE]

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