The Interaction of Insulin-Like Growth Factor Binding Protein 3 (IGFBP-3) in Insulin-Like Growth Factor (IGF)-Independent System

Insulin-like growth factor-binding protein 3 (IGFBP-3) is the most abundant IGFBP in circulation, interacts with high affinity to IGFs altering their function. Emerging evidence has indicated that IGFBP3 mostly involved in human disease such as diabetes, Alzheimer's disease, and cancer. It has been determined that IGFBP3 expression is decreased in various cancer cell lines by promoter methylation and proteases digestion. Therefore, bioavailable form of IGF-I increases in circulation promoting the tumorigenesis and progression of cancer. IGFBP3 function in cancer suppressing can be divided in two ways: IGF-dependent, and IGF-independent action. Recently it has been shown that IGFBP3 has vital roles independent of IGFs. Despite decades of unremitting research, this function of IGFBP-3 has not been clarified. However, it has been suggested that IGFBP3 independently can bind to its receptors in the nucleus including retinoid receptors (RXRs) peroxisome proliferator activated receptors (PPARγ), Nur77 vitamin D response (VDR), and/or cell surface receptors such as transmembrane protein 219 (TMEM219), low-density lipoprotein receptor-related protein 1 (LRP-1), and epidermal growth factor receptor (EGFR) inducing apoptosis. In this review, we described further mechanisms of IGF-independent action of IGFBP3.