Engineered ubiquitin ligase PTB-U-box targets insulin/insulin-like growth factor receptor for degradation and coordinately inhibits cancer malignancy
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Qinhao Wang1,*, Yi Ru1,*, Daixing Zhong2, Jing Zhang3, Libo Yao4 and Xia Li4
1 State Key Laboratory of Cancer Biology, Departments of Biochemistry and Molecular Biology, the Fourth Military Medical University, Xi’an, Shaanxi, China
2 Department of Thoracic Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi’an, Shaanxi, China
3 Experiment Teaching Center, the Fourth Military Medical University, Xi’an, Shaanxi, China
4 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
Xia Li, email:
Libo Yao, email:
Keywords: IGF-1R; IR; cancer therapy; engineered ubiquitin ligase; protein degradation
Received: March 17, 2014 Accepted: June 5, 2014 Published: June 6, 2014
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.
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