title: FOXM1 confers resistance to gefitinib in lung adenocarcinoma via a MET/AKT-dependent positive feedback loop.
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.
authors: Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.|Institute of Stomatology, Chinese PLA General Hospital, Beijing, China.
authors: Yu
authors: Y
authors: Wang
authors: Department of Biomedical Engineering, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Weiwei
authors: W
authors: Zhang
authors: Institute of Stomatology, Chinese PLA General Hospital, Beijing, China.
authors: Li
authors: L
authors: Wen
authors: Institute of Stomatology, Chinese PLA General Hospital, Beijing, China.
authors: Huiling
authors: H
authors: Yang
authors: Department of Pharmacy, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China.
authors: Mingling
authors: M
authors: Wen
authors: State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Yuyu
authors: Y
authors: Yun
authors: Institute of Stomatology, Chinese PLA General Hospital, Beijing, China.
authors: Lisheng
authors: L
authors: Zhao
authors: Department of Neurology, Kunming General Hospital, Chinese People's Liberation Army, Kunming, Yunnan, China.
authors: Xiaofei
authors: X
authors: Zhu
authors: Department of Anesthesiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Li
authors: L
authors: Tian
authors: Department of Biomedical Engineering, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Erping
authors: E
authors: Luo
authors: State Key Laboratory of Cancer Biology, Cell Engineering Research Center and Department of Cell Biology, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Yu
authors: Y
authors: Li
authors: Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Wenchao
authors: W
authors: Liu
authors: Institute of Stomatology, Chinese PLA General Hospital, Beijing, China.
authors: Ning
authors: N
authors: Wen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D025461:Feedback, Physiological; D000072278:Forkhead Box Protein M1 / Q000235:genetics / Q000378:metabolism*; D000077156:Gefitinib; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy*; D009025:Morpholines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism; D011799:Quinazolines / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D000970:Antineoplastic Agents; D002867:Chromones; D000072278:Forkhead Box Protein M1; D007211:Indoles; D009025:Morpholines; D011799:Quinazolines; D034741:RNA, Small Interfering; D013450:Sulfones; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib
keywords: AKT; FOXM1; MET; gefitinib; lung adenocarcinoma