Insulin-like growth factor 1 is a potent stimulator of cervical cancer cell invasiveness and proliferation that is modulated by αvβ3 integrin signaling

Meng Ru Shen, Yueh Mei Hsu, Keng Fu Hsu, Yih Fung Chen, Ming Jer Tang, Cheng Yang Chou

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Insulin-like growth factor 1 (IGF-1) has been implicated in promoting mitogenic, metastatic and antiapoptotic phenotypes in several types of cancer. But little is known about the signal interaction of IGF-1 and integrin in the regulation of cervical cancer development and progression. This study is to investigate the regulatory mechanism of IGF-1 receptor (IGF-1R) signaling and its importance in cervical cancer formation. The growth and invasiveness of cervical cancer cells (SiHa and CaSki) were dose-dependently stimulated by IGF-1, whereas those of normal cervical epithelial cells were not. The immunoblot showed that IGF-1R proteins were abundant in cervical cancer cell lines. In contrast, IGF-1R protein was nearly undetectable in normal cervical epithelial cells. IGF-1-stimulated invasion and proliferation were abolished by functional-blocking monoclonal antibody against IGF-1R, whereas these cellular functions were unaffected by either IgG or monoclonal antibody to insulin receptor. Functional-blocking monoclonal antibody against integrins αvβ3, but not α2, α3, α4, α6, β1, β4 or α2 β1, inhibited the IGF-1-stimulated invasion and proliferation in cervical cancer cells. αvβ3 integrin modulated IGF-1R phosphorylation by altering the rate of Src homology 2-containing phosphotyrosine phosphatase (SHP-2) recruitment to the activated IGF-1R. The modulation of αvβ3 occupancy also affected the activation of IGF-1R downstream-signaling elements, including activation of Akt and extracellular signal-regulated protein kinases 1/2 (Erk1/2). The treatment of blocking antibody of αvβ3 integrin or IGF-1R significantly inhibited tumor growth and caused tumor regression in SCID mice model. Immunoblots of tumor tissues confirmed that the phosphorylation of IGF-1R and downstream targets of Akt and Erk1/2 were remarkably decreased in SCID mice treated with blocking antibodies of αvβ3 or IGF-1R. Thus, these data suggest that the signal interaction between IGF-1R and αvβ3 integrin plays an important role in promoting the development and progression of cervical cancer.

Original languageEnglish
Pages (from-to)962-971
Number of pages10
JournalCarcinogenesis
Volume27
Issue number5
DOIs
Publication statusPublished - 2006 May 1

All Science Journal Classification (ASJC) codes

  • Cancer Research

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