Platelet-Derived Growth Factor (Pdgf)-Signaling Mediates Radiation-Induced Apoptosis In Human Prostate Cancer Cells With Loss Of P53 Function

Platelet-derived growth factor (PDGF) signals a diversity of cellular responses irt vitro, including cell proliferation, survival, transformation, and chemotaxis. PDGF functions as a ''competence factor'' to induce a set of early response genes expressed in G(1) including p21(WAF1/CIP1), a functional mediator of the tumor suppressor gene p53 in G(1)/S checkpoint, For PDGF-stimulated cells to progress beyond G(1) and transit the cell cycle completely, progression factors in serum such as insulin and IGF-1 are required, We have recently shown a novel role of PDGF in inducing apoptosis in growth-arrested murine fibroblasts, The PDGF-induced apoptosis is rescued by insulin, suggesting that G(1)/S checkpoint is a critical determinant for PDGF-induced apoptosis, Because recent studies suggest that radiation-induced signal transduction pathways interact with growth factor-mediated signaling pathways, we have investigated whether activation of the PDGF-signaling facilitates the radiation-induced apoptosis in the absence of functional p53, For this study we have used the 125-IL cell line, a mutant p53-containing, highly metastatic, and hormone-unresponsive human prostate carcinoma cell line, PDGF signaling is constitutively activated by transfection with a p28(v-sis) expression vector, which was previously shown to activate PDGF alpha- and beta-receptors, Although the basal level of p21(WAF1/CIP1) expression and radiation-induced apoptosis were not detectable in control 125-IL cells as would be predicted in mutant p53-containing cells, activation off PDGF-signaling induced expression of p21(WAF1/CIP1) and radiation-induced apoptosis, Our study suggests that the level of ''competence'' growth factors including PDGF may be one of the critical determinants for radiation-induced apoptosis, especially in cells with loss of p53 function at the site of radiotherapy in vivo. (C) 1997 Elsevier Science Inc.