title: Engineered ubiquitin ligase PTB-U-box targets insulin/insulin-like growth factor receptor for degradation and coordinately inhibits cancer malignancy.
abstract: The type 1 insulin-like growth factor receptor (IGF-1R) is a promising target for cancer therapy with antibodies and small molecule tyrosine kinase inhibitors (TKIs) which have been actively tested clinically. Evidences have demonstrated that insulin receptor (IR), which is implicated in tumorigenesis, conveys resistance to IGF-1R targeted therapy. This provided the compelling rationale for co-targeting IGF-1R and IR. Herein we have developed an approach to simultaneously down-regulate IGF-1R and IR in protein levels. By generating and screening several engineered ubiquitin ligases, we have identified that, PTB-U-box, which is composed of an IGF-1R/IR-binding domain and a functional E3 ubiquitin ligase domain, binds activated IGF-1R/IR and targets their ubiquitination and degradation. When ectopically expressed in HepG2 and HeLa cells, PTB-U-box inhibits cell proliferation and invasion, increases chemo-sensitivity, as well as interrupts glucose metabolism. Finally, intratumoral injection of adenovirus carrying PTB-U-box dramatically retards the growth of HepG2 xenograft. Therefore, well-designed engineered ubiquitin ligase represents an effective therapeutic strategy for the treatment of the cancers with co-expressed IGF-1R/IR.
authors: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an, Shaanxi, China. These authors contributed equally to this work.
authors: Qinhao
authors: Q
authors: Wang
authors: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an, Shaanxi, China. These authors contributed equally to this work.
authors: Yi
authors: Y
authors: Ru
authors: Department of Thoracic Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Daixing
authors: D
authors: Zhong
authors: Experiment Teaching Center, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Jing
authors: J
authors: Zhang
authors: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Libo
authors: L
authors: Yao
authors: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi'an, Shaanxi, China.
authors: Xia
authors: X
authors: Li
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D015552:Injections, Intralesional; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D015202:Protein Engineering / Q000379:methods; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D044767:Ubiquitin-Protein Ligases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin