Overexpression of insulin-like growth factor binding protein-5 helps accelerate progression to androgen-independence in the human prostate LNCaP tumor model through activation of phosphatidylinositol 3 '-kinase pathway

Although insulin-like growth factor (IGF) binding protein-5 (IGFBP-5) is hi ghly up-regulated in normal and malignant pros tate tissues after androgen withdrawal, its functional role in castration-induced apoptosis and androge n-independent progression remains undefined. To analyze the functional sign ificance of IGFBP-5 overexpression in IGF-I-mediated mitogenesis and progre ssion to androgen-independence, IGFBP-5-overexpressing human androgen-depen dent LNCaP prostate cancer cells were generated by stable transfection. The growth rates of IGFBP-5-transfected LNCaP cells were significantly faster, compared with either the parental or vector-only transfected LNCaP cells i n both the presence and absence of dihydrotestosterone. IGFBP-5-induced inc reases in LNCaP cell proliferation occurs through both IGF-I-dependent and -independent pathways, with corresponding increases in the cyclin D1 messen ger RNA expression and the fraction of cells in S + G2/M phases of the cell cycle. Changes in Akt/protein kinase B, a downstream component of phosphat idyl-inositol 3'-kinase (PI3K) pathway, in the LNCaP sublines also parallel ed changes in their growth rates. Although treatment with a PI3K inhibitor induced apoptosis in both control and IGFBP-5-overexpressing LNCaP cells, t his PI3K inhibitor-induced apoptosis was prevented by exogenous IGF-I treat ment only in IGFBP-5 transfectants, suggesting that IGFBP-5 overexpression can potentiate the antiapoptotic effects of IGF-I. Furthermore, tumor growt h and serum prostate-specific antigen levels increased several fold faster in mice bearing IGFBP-5-transfected LNCaP tumors after castration, despite having similar tumor incidence and tumor growth rates with controls when gr own in intact mice before castration. Collectively, these data suggest that IGFBP-5 overexpression in prostate cancer cells after castration is an ada ptive cell survival mechanism that helps potentiate the antiapoptotic and m itogenic effects of IGF-I, thereby accelerating progression to androgen ind ependence through activation of the PI3K-Akt/protein kinase B signaling pat hway.