Dataset Information

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

ABSTRACT: 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 ?2?2 receptor, in which the ? subunits comprise the ligand binding site, whereas the ? 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 ? (aa 1-524) and ? (aa 741-936) subunits, and found that either dnIGF1R? and/or dnIGF1R? effectively inhibited cell migration, colony formation, and cell cycle progression of human OS cells, which could be reversed by exogenous IGF1. Furthermore, dnIGF1R? and/or dnIGF1R? inhibited OS xenograft tumor growth in vivo, with the greatest inhibition of tumor growth shown by dnIGF1R?. 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?, may be further developed as novel anticancer agents that target IGF signaling axis with high specificity and efficacy.

SUBMITTER: Cao D

PROVIDER: S-EPMC7642656 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Cao Daigui D Lei Yan Y Ye Zhenyu Z Zhao Ling L Wang Hao H Zhang Jing J He Fang F Huang Linjuan L Shi Deyao D Liu Qing Q Ni Na N Pakvasa Mikhail M Wagstaff William W Zhao Xia X Fu Kai K Tucker Andrew B AB Chen Connie C Reid Russell R RR Haydon Rex C RC Luu Hue H HH He Tong-Chuan TC Liao Zhan Z

American journal of cancer research 20201001 10

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 ...[more]

PMID: 33163268

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Dataset Information

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

Publications

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

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