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 signalling pathway. In body fluids, IGFs are sequestered by IGF binding proteins (IGFBPs), and hence the availability of IGFs for bioactivity are modulated by IGFBPs. In recent years, it has become clear that IGFBPs also exert effects on cell growth, independent o their ability to bind IGFs, and presumably through association with the cell surface. Both the IGF-dependent and IGF- independent actions of IGFBPs can be further modulated by IGFBP proteases. Thus, it is clear that IGFBPs play integral roles in cell growth, either through modulation of IGF bioavailability, or through their own actions on cell proliferation. Our laboratory was among the first to characterize the IGF system in the prostate. We and others have detected IGF-ll, type I IGF receptors, IGFBPs, and IGFBP proteases (prostate specific antigen, urokinase-type plasminogen activator, and cathepsin D) in normal, as well as malignant prostate. IGFBP expression, in particular IGFBP-2, -3 and -5, is altered by malignancy, although the signals, the molecular mechanism(s) leading to altered IGFBP expression and the consequences of altered IGFBP expression on prostate carcinogenesis, are not known. We have also recently identified a new IGFBP (designated IGFBP-7) in prostate whose, expression is significantly decreased in cancer cells. Thus, our central hypothesis is INSULIN-LIKE GROWTH FACTOR BINDING PROTEINS ARE MAJOR REGULATORS OF PROSTATIC CELL GROWTH. In order to better understand the roles of IGFBPs in the regulation of normal and malignant prostate growth, we propose to (I) determine the regulation mechanisms of key IGFBPs in prostatic cancer cell lines; (2) demonstrate that IGFBPs act as regulators and modulators of prostatic cell growth, through both IGF-dependent and IGF- independent mechanism(s); (3) demonstrate that proteolysis of key prostatic IGFBPs not only alters the affinity of the IGFBP for IGFs, but results in IGFBP fragments capable of exerting biological effects on prostate cell growth; and (4) characterize and study the regulation of the new IGFBP (IGFBP-7) in the prostate.
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