Abstract
We previously reported that IGF binding protein-3 (IGFBP-3), a major IGF-binding protein in human serum, regulates angiogenic activities of human head and neck squamous cell carcinoma (HNSCC) cells and human umbilical vein endothelial cells (HUVECs) through IGF-dependent and IGF-independent mechanisms. However, the role of IGFBP-3 in cell adhesion is largely unknown. We demonstrate here that IGFBP-3 inhibits the adhesion of HNSCC cells and HUVECs to the extracellular matrix (ECM). IGFBP-3 reduced transcription of a variety of integrins, especially integrin β4, and suppressed phosphorylation of focal adhesion kinase (FAK) and Src in these cells through both IGF-dependent and IGF-independent pathways. IGFBP-3 was found to suppress the transcription of c-fos and c-jun and the activity of AP1 transcription factor. The regulatory effect of IGFBP-3 on integrin β4 transcription was attenuated by blocking c-jun and c-fos gene expression via siRNA transfection. Taken together, our data show that IGFBP-3 has IGF-dependent and -independent inhibitory effects on intracellular adhesion signaling in HNSCC and HUVECs through its ability to block c-jun and c-fos transcription and thus AP-1-mediated integrin β4 transcription. Collectively, our data suggest that IGFPB-3 may be an effective cancer therapeutic agent by blocking integrin-mediated adhesive activity of tumor and vascular endothelial cells.
Highlights
The integrin superfamily is a major class of cell surface receptors for extracellular matrix (ECM) molecules
To further study the effects of IGF binding protein-3 (IGFBP-3) on tumor growth and progression, we investigated whether IGFBP-3 can alter cancer cell adhesion to ECM
UMSCC38 cells expressing shIGFBP-3 exhibited increased binding to fibronectin, type I collagen, laminin, and gelatin compared with shGFP-expressing cells; this increased binding was reversed by Recombinant human IGF-I and IGFBP-3 (rBP3) treatment (Figure 1B)
Summary
The integrin superfamily is a major class of cell surface receptors for ECM molecules. Members of this superfamily are composed of α and β subunits. Endothelial cells express a variety of integrins, including α5β1, αvβ and αvβ, which are receptors for fibronectin (FN); α3β1, α6β1, and α6β4, which are receptors for laminin; and αvβ, which is a receptor for vitronectin, osteopontin, and collagen [2]. Integrins play an important role in cell-cell and cell-matrix adhesion and are involved in tumor growth and metastasis through numerous cellular functions, including cell migration, invasion, and extravasation [3]. Targeting integrin-mediated signaling may represent a powerful anticancer therapy [5]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
