Insulin-Like Growth Factor Binding Protein-3 Exerts Its Anti-Metastatic Effect in Aerodigestive Tract Cancers by Disrupting the Protein Stability of Vimentinopen access
- Authors
- Le, Huong Thuy; Lee, Ho Jin; Cho, Jaebeom; Min, Hye-Young; Lee, Ji-Sun; Lee, Su-Jae; Lee, Ho-Young
- Issue Date
- Mar-2021
- Publisher
- MDPI
- Keywords
- insulin-like growth factor binding protein-3; vimentin; metastasis
- Citation
- CANCERS, v.13, no.5, pp.1 - 25
- Indexed
- SCIE
SCOPUS
- Journal Title
- CANCERS
- Volume
- 13
- Number
- 5
- Start Page
- 1
- End Page
- 25
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/1335
- DOI
- 10.3390/cancers13051041
- ISSN
- 2072-6694
- Abstract
- Simple Summary Local invasion and distal metastasis are the main causes of cancer-related death and the poor prognosis of patients with aerodigestive tract cancers. Therefore, understanding the biology of invasion and metastasis is important for the development of effective therapeutic strategies. The present study shows that insulin-like growth factor binding protein-3 (IGFBP-3) inhibits the migration and invasion of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) cells in vitro and the development of metastasized tumors in vivo. Mechanistic studies suggest vimentin as a cellular target for the antimetastatic effect of IGFBP-3. These results contribute to a better understanding on the regulation of metastasis of cancer cells, providing the rationale to utilize IGFBP-3 as an effective therapeutic strategy targeting migration and metastasis of aerodigestive tract cancers. The proapoptotic, antiangiogenic, and antimetastatic activities of insulin-like growth factor binding protein-3 (IGFBP-3) through IGF-dependent or -independent mechanisms have been suggested in various types of human cancers. However, a mechanistic explanation of and downstream targets involved in the antimetastatic effect of IGFBP-3 is still lacking. In this study, by applying various in vitro and in vivo models, we show that IGFBP-3 suppresses migration and invasion of human head and neck squamous carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) cells. Silencing IGFBP-3 expression elevated the migration and invasion of NSCLC and HNSCC cells in vitro and their local invasion and metastasis in vivo, whereas overexpression of IGFBP-3 decreased such prometastatic changes. Local invasion of 4-nitroquinoline-1-oxide (4-NQO)-induced HNSCC tumors was consistently significantly potentiated in Igfbp3 knockout mice compared with that in wild-type mice. Mechanistically, IGFBP-3 disrupted the protein stability of vimentin via direct binding and promoting its association with the E3 ligase FBXL14, causing proteasomal degradation. The C-terminal domain of IGFBP-3 and the head domain of vimentin are essential for their interaction. These results provide a molecular framework for IGFBP-3 ' s IGF-independent antimetastatic and antitumor activities.
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