Chimeric ubiquitin ligases inhibit non-small cell lung cancer via negative modulation of EGFR signaling

被引:17
作者
Zhong, Daixing [1 ,2 ]
Ru, Yi [1 ]
Wang, Qinhao [1 ]
Zhang, Jing [3 ]
Zhang, Jian [1 ]
Wei, Junxia [4 ,5 ]
Wu, Jin [6 ]
Yao, Libo [1 ]
Li, Xiaofei [2 ]
Li, Xia [1 ]
机构
[1] Fourth Mil Med Univ, Dept Biochem & Mol Biol, State Key Lab Canc Biol, Xian 710032, Shaanxi, Peoples R China
[2] Fourth Mil Med Univ, Tangdu Hosp, Dept Thorac Surg, Xian 710038, Shaanxi, Peoples R China
[3] Fourth Mil Med Univ, Expt Teaching Ctr, Xian 710032, Shaanxi, Peoples R China
[4] Fourth Mil Med Univ, Tangdu Hosp, Dept Clin Lab, Xian 710038, Shaanxi, Peoples R China
[5] Fourth Mil Med Univ, Tangdu Hosp, Res Ctr, Xian 710038, Shaanxi, Peoples R China
[6] Xiamen Univ, Affiliated Southeast Hosp, Dept Orthopaed, Fujian 363000, Peoples R China
基金
中国国家自然科学基金;
关键词
NSCLC; EGFR; Ubiquitination; Targeted therapy; EPIDERMAL-GROWTH-FACTOR; TYROSINE KINASE INHIBITORS; FACTOR RECEPTOR EXPRESSION; U-BOX PROTEINS; ACQUIRED-RESISTANCE; GEFITINIB; FAMILY; DEGRADATION; TRANSFORMATION; MUTATIONS;
D O I
10.1016/j.canlet.2014.12.043
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
Targeting epidermal growth factor receptor (EGFR) represents a promising therapeutic strategy for non-small cell lung cancers (NSCLC). The ubiquitin proteasome system (UPS) is a major pathway that mediates protein degradation. To target the degradation of EGFR, we generated two artificial ubiquitin ligases, which are composed of an EGFR-binding domain, i.e., the SH2 domain from growth factor receptor binding protein 2 (Grb2), and an ubiquitin ligase catalytic domain, i.e., the RING domain from Cbl or the U-box domain from CHIP. When the chimeric ubiquitin ligases were introduced into lung cancer SPC-A1 cells, they effectively associated with EGFR, promoted its ubiquitination and degradation, and as a result, blocked the downstream PI3K-Akt signal pathway. Moreover, cell proliferation and invasion were inhibited, the sensitivity to docetaxel-induced apoptosis was enhanced and the tumorigenicity was suppressed. In conclusion, negative modulation of EGFR signaling by the chimeric ubiquitin ligases can inhibit malignancy of SPC-A1 cells and sensitize these cells to chemotherapy, thus it may be applied to targeted therapy for NSCLC. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:57 / 64
页数:8
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