title: Chimeric ubiquitin ligases inhibit non-small cell lung cancer via negative modulation of EGFR signaling.
abstract: 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.
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China; Department of Thoracic Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
authors.forename: Daixing
authors.initials: D
authors.lastname: Zhong
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Ru
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Qinhao
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Experiment Teaching Center, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Clinical Laboratory and Research Center, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
authors.forename: Junxia
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Orthopaedics, the Affiliated Southeast Hospital of Xiamen University, Zhangzhou, Fujian 363000, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Libo
authors.initials: L
authors.lastname: Yao
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710038, China. Electronic address: lxfchest@fmmu.edu.cn.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an, Shaanxi 710032, China. Electronic address: lixia@fmmu.edu.cn.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D054875:Ubiquitination; D018909:src Homology Domains
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D004317:Doxorubicin; D044767:Ubiquitin-Protein Ligases; D058539:Phosphatidylinositol 3-Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt
keywords: EGFR; NSCLC; Targeted therapy; Ubiquitination