title: Insulin-like growth factor 1 is a potent stimulator of cervical cancer cell invasiveness and proliferation that is modulated by alphavbeta3 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 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.
authors.affiliation: Department of Pharmacology, National Cheng Kung University, Tainan 704, Taiwan.
authors.forename: Meng-Ru
authors.initials: MR
authors.lastname: Shen
authors.forename: Yueh-Mei
authors.initials: YM
authors.lastname: Hsu
authors.forename: Keng-Fu
authors.initials: KF
authors.lastname: Hsu
authors.forename: Yih-Fung
authors.initials: YF
authors.lastname: Chen
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tang
authors.forename: Cheng-Yang
authors.initials: CY
authors.lastname: Chou
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000502:physiology*; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010766:Phosphorylation; D015398:Signal Transduction; D013997:Time Factors; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: D039302:Integrin alphaVbeta3; D007334:Insulin-Like Growth Factor I