Isfahan University of Medical Sciences Journal of Isfahan Medical School 1027-7595 35 451 2017 11 22 The Interaction of Insulin-Like Growth Factor Binding Protein 3 (IGFBP-3) in Insulin-Like Growth Factor (IGF)-Independent System The Interaction of Insulin-Like Growth Factor Binding Protein 3 (IGFBP-3) in Insulin-Like Growth Factor (IGF)-Independent System 1452 1461 15391 FA Amir Ansari MSc Student, Department of Medical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran Ali Gheysarzadeh PhD Student, Department of Medical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran Mohammad Reza Mofid Associate Professor, Department of Medical Biochemistry, School of Pharmacy and Pharmaceutical Sciences AND Bioinformatics Research Center, Isfahan University of Medical Sciences, Isfahan, Iran 0000-0002-0347-8152 Journal Article 2017 09 25 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. 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. https://jims.mui.ac.ir/article_15391_0b8becede7a3559aa2deeff99c51d9c6.pdf