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 alpha(v)beta3, but not alpha2 alpha3, alpha4 alpha6 beta1, beta4 or alpha2beta1, inhibited the IGF-1-stimulated invasion and proliferation in
cervical cancer cells. alpha(v)
beta3 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 alpha(v)beta3 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 alpha(v)
beta3 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 alpha(v)beta3 or IGF-1R. Thus, these data suggest that the signal interaction between IGF-1R and alpha(v)
beta3 integrin plays an important role in promoting the development and progression of
cervical cancer.