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

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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

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IGF Type 1 Receptor
Somatomedins
Integrins
Uterine Cervical Neoplasms
Cell Proliferation
Blocking Antibodies
Mitogen-Activated Protein Kinase 3
SCID Mice
Monoclonal Antibodies
Protein Kinases
Neoplasms
Epithelial Cells
Phosphorylation
Somatomedin Receptors
Protein Tyrosine Phosphatases
Insulin Receptor
Growth
Proteins
Immunoglobulin G
Phenotype

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

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title = "Insulin-like growth factor 1 is a potent stimulator of cervical cancer cell invasiveness and proliferation that is modulated by αvβ3 integrin signaling",
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.",
author = "Meng-Ru Shen and Hsu, {Yueh Mei} and Keng-Fu Hsu and Chen, {Yih Fung} and Ming-Jer Tang and Cheng-Yang Chou",
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AU - Hsu, Yueh Mei

AU - Hsu, Keng-Fu

AU - Chen, Yih Fung

AU - Tang, Ming-Jer

AU - Chou, Cheng-Yang

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N2 - 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.

AB - 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.

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