Oncotarget

Research Papers:

FOXM1 confers resistance to gefitinib in lung adenocarcinoma via a MET/AKT-dependent positive feedback loop

Yu Wang, Weiwei Zhang, Li Wen, Huiling Yang, Mingling Wen, Yuyu Yun, Lisheng Zhao, Xiaofei Zhu, Li Tian, Erping Luo, Yu Li, Wenchao Liu and Ning Wen _

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Oncotarget. 2016; 7:59245-59259. https://doi.org/10.18632/oncotarget.11043

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Abstract

Yu Wang1,2,*, Weiwei Zhang3,*, Li Wen2,*, Huiling Yang2,*, Mingling Wen4, Yuyu Yun5, Lisheng Zhao2, Xiaofei Zhu6, Li Tian7, Erping Luo3, Yu Li5, Wenchao Liu1, Ning Wen2

1Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China

2Institute of Stomatology, Chinese PLA General Hospital, Beijing, China

3Department of Biomedical Engineering, The Fourth Military Medical University, Xi'an, Shaanxi, China

4Department of Pharmacy, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China

5State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, The Fourth Military Medical University, Xi'an, Shaanxi, China

6Department of Neurology, Kunming General Hospital, Chinese People's Liberation Army, Kunming, Yunnan, China

7Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China

*These authors contributed equally to this work

Correspondence to:

Yu Li, email: liyufmmu@yahoo.com

Wenchao Liu, email: xjcancer@fmmu.edu.cn

Ning Wen, email: wenningchn@163.com

Keywords: FOXM1, MET, AKT, lung adenocarcinoma, gefitinib

Received: January 20, 2016     Accepted: July 18, 2016     Published: August 03, 2016

ABSTRACT

Gefitinib resistance remains a major problem in the treatment of lung adenocarcinoma. However, the molecular mechanisms of gefitinib resistance are not fully understood. In this study, we characterized the critical role of transcription factor Forkhead box protein M1 (FOXM1) in gefitinib resistance of lung adenocarcinoma cells. In vitro drug sensitivity assays demonstrated that FOXM1 inhibition sensitized PC9/GR and HCC827/GR cells to gefitinib, whereas FOXM1 overexpression enhanced PC9 and HCC827 cell resistance to gefitinib. Increased FOXM1 resulted in the upregulation of hepatocyte growth factor receptor (MET), which led to activation of the protein kinase B (AKT) pathway, whereas knockdown of FOXM1 did the opposite. FOXM1 bound directly to the MET promoter regions and regulated the promoter activities and the expression of MET at the transcriptional level. Moreover, MET/AKT pathway upregulated the expression of FOXM1 in lung adenocarcinoma cells. Inhibition of pAKT by LY294002 or inhibition of pMET by PHA-665752 significantly inhibited the expression of FOXM1 in lung adenocarcinoma cells. Importantly, we further demonstrated that the expression levels of FOXM1, pAKT and MET were significantly increased in lung adenocarcinoma tissues relative to normal lung tissues, and these three biomarkers were concomitantly overexpressed in lung adenocarcinoma tissues. Taken together, our results indicate that FOXM1 promotes acquired resistance to gefitinib of lung adenocarcinoma cells, and FOXM1 crosstalks with MET/AKT signaling to form a positive feedback loop to promote lung adenocarcinoma development.


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