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Unraveling Insulin-Like Growth Factor Binding Protein-3 Actions in Human Disease

Department of Pathology (S.J.-B., Y.O.), Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298; and Department of Medicine, Division of Endocrinology (D.F.), Stanford University, Stanford, California 94305

Correspondence: Address all correspondence and requests for reprints to: Dr. Youngman Oh, Department of Pathology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia 23298-0662. E-mail: yoh{at}vcu.edu.

The IGF system plays critical roles in somatic growth in an endocrine fashion (somatomedin hypothesis) as well as proliferation and differentiation of normal and malignant cells in a paracrine/autocrine fashion. IGFBP-3 is known to modulate the actions of IGFs in circulation as well as the immediate extracellular environment. Interestingly, apart from the ability to inhibit or enhance IGF actions, IGFBP-3 also exhibits very clear, distinct biological effects independent of the IGF/IGF-I receptor axis. Over the past decade it has become widely appreciated that IGF/IGF-IR-independent actions of IGFBP-3 (antiproliferative and proapoptotic effects) contribute to improving the pathophysiology of a variety of human diseases, such as cancer, diabetes, and malnutrition. Recent studies have implicated interaction of IGFBP-3 with a variety of proteins or signaling cascades critical to cell cycle control and apoptosis; however, the actual mechanism of IGFBP-3 action is still unclear. This review reinforces the concept in support of the IGF/IGF-IR axis-independent actions of IGFBP-3 and delineates potential underlying mechanisms involved and subsequent biological significance, focusing in particular on functional binding partners and the clinical significance of IGFBP-3 in the assessment of cancer risk.