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Insulin-like growth factor binding protein-3 inhibits cell adhesion via suppression of integrin β4 expression

2015; Impact Journals LLC; Volume: 6; Issue: 17 Linguagem: Inglês

10.18632/oncotarget.3825

1949-2553

HJ Lee, Jisun Lee, Su Jung Hwang, Ho‐Young Lee,

Cancer, Hypoxia, and Metabolism

// Hyo-Jong Lee 1,2,3 , Ji-Sun Lee 4 , Su Jung Hwang 1 and Ho-Young Lee 4 1 College of Pharmacy, Inje University, Gimhae, Gyungnam, Republic of Korea 2 u-Healthcare and Anti-aging Research Center (u-HARC), Inje University, Gimhae, Republic of Korea 3 Biohealth Products Research Center (BPRC), Inje University, Gimhae, Republic of Korea 4 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea Correspondence to: Ho-Young Lee, email: // Keywords : IGFBP-3, IGF-1, integrin, cell adhesion, AP-1, angiogenesis Received : December 18, 2014 Accepted : March 26, 2015 Published : April 14, 2015 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 β 4 , 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 β 4 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 β 4 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.