Prostate carcinogenesis involves loss of the normal growth regulatory machinery, which encompasses the complex regulation of androgenic hormones and multiple growth factors, including IGFs (insulin-like growth factors). IGFs (IGF-I and IGF-II), which exert endocrine, paracrine and autocrine effects on cell proliferation, stimulate cell growth through the type I IGF receptor signaling pathway. In body fluids, IGFs are sequestered by IGF binding proteins (IGFBPs), and hence the availability of IGFs for bioactivity is modulated by IGFBPs. IGFBPs can also exert effects on cell growth, independent of their ability to bind IGFs, presumably through association with the cell surface. The IGF-independent actions of the IGFBPs have been supported, in part, by recent identification of proteins that are structurally and functionally related to the IGFBPs. Together, it has become clear that IGFBPs and the IGFBP related proteins (IGFBP-rPs) play integral roles in cell growth, either through modulation of IGF bioavailability or through IGF-independent actions on cell proliferation. Prostate cancer cells, unlike normal cells, do not undergo senescence, differentiation or programmed cell death (apoptosis). The cellular machinery necessary to activate these pathways, however, is retained. In the progression to carcinogenesis, expression of particularly IGFBP-3 and Mac25/IGFBP-rP1 are down-regulated, and their over-expression in prostate cancer cells result in growth arrest and induction of apoptosis and/or differentiation. Our central hypothesis is, therefore, that INSULIN-LIKE GROWTH FACTOR BINDING PROTEINS AND RELATED PROTEINS ARE MAJOR REGULATORS OF PROSTATIC CELL GROWTH. Although the anti-proliferative and pro-apoptotic activities of the IGFBPs and IGFBP-rPs are of critical importance in prostate cancer, the mechanism(s) of action is poorly understood. Hence we propose to: (1) elucidate the mechanism(s) by which IGFBP-3 inhibit growth and induce apoptosis in prostate cells; (2) determine the transcriptional regulation of IGFBP-3 in prostate cancer cells; and (3) determine the role of Mac25/IGFBP-rPl in anti-proliferation and neuroendocrinelike differentiation of prostate cancer cell.
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