Blockade of IGF/IGF-1R signaling axis with soluble IGF-1R mutants suppresses the cell proliferation and tumor growth of human osteosarcoma

被引:1
|
作者
Cao, Daigui [1 ,2 ,3 ]
Lei, Yan [2 ,4 ]
Ye, Zhenyu [2 ,5 ]
Zhao, Ling [2 ,4 ]
Wang, Hao [2 ,6 ,7 ]
Zhang, Jing [2 ,4 ]
He, Fang [2 ,4 ]
Huang, Linjuan [2 ,4 ]
Shi, Deyao [2 ,8 ]
Liu, Qing [2 ,9 ]
Ni, Na [2 ,6 ,7 ]
Pakvasa, Mikhail [2 ]
Wagstaff, William [2 ]
Zhao, Xia [2 ,10 ]
Fu, Kai [2 ,11 ]
Tucker, Andrew B. [2 ]
Chen, Connie [2 ]
Reid, Russell R. [2 ,12 ]
Haydon, Rex C. [2 ]
Luu, Hue H. [2 ]
He, Tong-Chuan [2 ]
Liao, Zhan [2 ,13 ]
机构
[1] Chongqing Med Univ, Dept Orthopaed Surg, Affiliated Hosp 2, Chongqing, Peoples R China
[2] Univ Chicago, Med Ctr, Mol Oncol Lab, Dept Orthopaed Surg & Rehabil Med, Chicago, IL 60637 USA
[3] Univ Chinese Acad Sci, Dept Orthopaed Surg, Chongqing Gen Hosp, Chongqing, Peoples R China
[4] Chongqing Med Univ, Dept Otolaryngol Obstet & Gynecol & Nephrol, Affiliated Hosp 1, Chongqing, Peoples R China
[5] Soochow Univ, Dept Gen Surg, Affiliated Hosp 2, Suzhou, Peoples R China
[6] Chongqing Med Univ, Minist Educ, Key Lab Diagnost Med, Chongqing, Peoples R China
[7] Chongqing Med Univ, Sch Lab & Diagnost Med, Chongqing, Peoples R China
[8] Huazhong Univ Sci & Technol, Union Hosp, Dept Orthopaed, Tongji Med Coll, Wuhan, Peoples R China
[9] Cent South Univ, Xiangya Hosp 2, Dept Spine Surg, Changsha, Peoples R China
[10] Qingdao Univ, Dept Orthopaed Surg, Affiliated Hosp, Qingdao, Peoples R China
[11] Wuhan Univ, Dept Neurosurg, Affiliated Zhongnan Hosp, Wuhan, Peoples R China
[12] Univ Chicago, Med Ctr, Dept Surg, Sect Plast & Reconstruct Surg, Chicago, IL 60637 USA
[13] Cent South Univ, Dept Orthopaed Surg, Xiangya Hosp, Changsha 410000, Peoples R China
来源
AMERICAN JOURNAL OF CANCER RESEARCH | 2020年 / 10卷 / 10期
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
Osteosarcoma; bone tumor; IGF-1R; IGF signaling dominant-negative mutants; targeted therapy; MESENCHYMAL STEM-CELLS; FACTOR RECEPTOR FAMILY; SIMPLIFIED SYSTEM; INHIBITS GROWTH; BONE-FORMATION; CANCER-CELLS; INSULIN; DIFFERENTIATION; PROTEIN; METASTASIS;
D O I
暂无
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Primary bone tumor, also known as osteosarcoma (OS), is the most common primary malignancy of bone in children and young adults. Current treatment protocols yield a 5-year survival rate of near 70% although approximately 80% of patients have metastatic disease at the time of diagnosis. However, long-term survival rates have remained virtually unchanged for nearly four decades, largely due to our limited understanding of the disease process. One major signaling pathway that has been implicated in human OS tumorigenesis is the insulin-like growth factor (IGF)/insulin-like growth factor-1 receptor (IGF1R) signaling axis. IGF1R is a heterotetrameric alpha 2 beta 2 receptor, in which the a subunits comprise the ligand binding site, whereas the beta subunits are transmembrane proteins containing intracellular tyrosine kinase domains. Although numerous strategies have been devised to target IGF/IGF1R axis, most of them have failed in clinical trials due to the lack of specificity and/or limited efficacy. Here, we investigated whether a more effective and specific blockade of IGF1R activity in human OS cells can be accomplished by employing dominant-negative IGF1R (dnIGF1R) mutants. We engineered the recombinant adenoviruses expressing two IGF1R mutants derived from the alpha (aa 1-524) and beta (aa 741-936) subunits, and found that either dnIGF1Ra and/or dnIGF1R beta effectively inhibited cell migration, colony formation, and cell cycle progression of human OS cells, which could be reversed by exogenous IGF1. Furthermore, dnIGF1R alpha and/or dnIGF1R beta inhibited OS xenograft tumor growth in vivo, with the greatest inhibition of tumor growth shown by dnIGF1R alpha. Mechanistically, the dnIGF1R mutants down-regulated the expression of PI3K/AKT and RAS/RAF/MAPK, BCL2, Cyclin D1 and most EMT regulators, while up-regulating pro-apoptotic genes in human OS cells. Collectively, these findings strongly suggest that the dnIGF1R mutants, especially dnIGF1R alpha, may be further developed as novel anticancer agents that target IGF signaling axis with high specificity and efficacy.
引用
收藏
页码:3248 / +
页数:21
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