Xia Fang1, Pan Gu2, Caicun Zhou3, Aibin Liang4, Shenxiang Ren5, Fang Liu6, Yu Zeng7, Yunjin Wu8, Yinmin Zhao9, Binbin Huang10, Zongmei Zhang11, Xianghua Yi12. 1. Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. Electronic address: dilay_123@yahoo.cn. 2. Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. Electronic address: gupanjiayou@sina.com. 3. Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China. Electronic address: cczhou2000@126.com. 4. Department of Haematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. Electronic address: lab410817@126.com. 5. Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China. Electronic address: Hillary_ren@126.com. 6. Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. Electronic address: GYLIUFANG@HOTMAIL.COM. 7. Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. Electronic address: yuzeng77@hotmail.com. 8. Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. Electronic address: yunjinwuhope@126.com. 9. Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China. Electronic address: zhaoyingmin80@126.com. 10. Department of Haematology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. Electronic address: binbin2004_20@hotmail.com. 11. Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. Electronic address: zongzong1986@126.com. 12. Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China. Electronic address: yixhxf@yahoo.com.cn.
Abstract
BACKGROUND: Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) presents great challenges in the treatment of non-small cell lung cancer (NSCLC) patients, while the mechanisms are still not well understood. The β-catenin signaling pathway has been found to be associated with chemoresistance and can activate the EGFR and its downstream pathways. This study aimed to investigate the role of β-catenin in acquired resistance to EGFR-TKIs in NSCLC cell lines. METHODS: The expression and transcriptional activity of β-catenin were measured in both the NSCLC cell line PC9 and its sub-line PC9/AB(2) which has acquired resistance to gefitinib. Knockdown and overexpression of β-catenin in the PC9/AB(2) and PC9 cells were performed. The cell survival rate and the activation of the EGFR and its downstream pathways were detected in the two cell lines after transfection. RESULTS: Nuclear translocation of β-catenin was increased in the PC9/AB(2) cells and the baseline expression of members of the β-catenin signaling pathway was also higher in the PC9/AB(2) cells. Knocking down the expression of β-catenin increased the sensitivity of the PC9/AB(2) cells to gefitinib by blocking the activation of the EGFR downstream pathways, while β-catenin overexpression improved PC9 cells resistance to gefitinib by enhancing the activation of the EGFR and its downstream signaling. CONCLUSION: β-catenin plays an important role in acquired resistance to EGFR-TKIs in NSCLC cell lines and may be a potential therapeutic target for NSCLC patients who have failed to respond to targeted therapy. Crown
BACKGROUND: Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) presents great challenges in the treatment of non-small cell lung cancer (NSCLC) patients, while the mechanisms are still not well understood. The β-catenin signaling pathway has been found to be associated with chemoresistance and can activate the EGFR and its downstream pathways. This study aimed to investigate the role of β-catenin in acquired resistance to EGFR-TKIs in NSCLC cell lines. METHODS: The expression and transcriptional activity of β-catenin were measured in both the NSCLC cell line PC9 and its sub-line PC9/AB(2) which has acquired resistance to gefitinib. Knockdown and overexpression of β-catenin in the PC9/AB(2) and PC9 cells were performed. The cell survival rate and the activation of the EGFR and its downstream pathways were detected in the two cell lines after transfection. RESULTS: Nuclear translocation of β-catenin was increased in the PC9/AB(2) cells and the baseline expression of members of the β-catenin signaling pathway was also higher in the PC9/AB(2) cells. Knocking down the expression of β-catenin increased the sensitivity of the PC9/AB(2) cells to gefitinib by blocking the activation of the EGFR downstream pathways, while β-catenin overexpression improved PC9 cells resistance to gefitinib by enhancing the activation of the EGFR and its downstream signaling. CONCLUSION: β-catenin plays an important role in acquired resistance to EGFR-TKIs in NSCLC cell lines and may be a potential therapeutic target for NSCLCpatients who have failed to respond to targeted therapy. Crown
Authors: Paola Moreno; Samuel A Mantey; Suk H Lee; Irene Ramos-Álvarez; Terry W Moody; Robert T Jensen Journal: Peptides Date: 2018-02-02 Impact factor: 3.750