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, transform ation, and chemotaxis. PDGF functions as a ''competence factor'' to in duce a set of early response genes expressed in G(1) including p21(WAF 1/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 a s insulin and IGF-1 are required, We have recently shown a novel role of PDGF in inducing apoptosis in growth-arrested murine fibroblasts, T he PDGF-induced apoptosis is rescued by insulin, suggesting that G(1)/ S checkpoint is a critical determinant for PDGF-induced apoptosis, Bec ause 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 ac tivate PDGF alpha- and beta-receptors, Although the basal level of p21 (WAF1/CIP1) expression and radiation-induced apoptosis were not detect able in control 125-IL cells as would be predicted in mutant p53-conta ining cells, activation off PDGF-signaling induced expression of p21(W AF1/CIP1) and radiation-induced apoptosis, Our study suggests that the level of ''competence'' growth factors including PDGF may be one of t he critical determinants for radiation-induced apoptosis, especially i n cells with loss of p53 function at the site of radiotherapy in vivo. (C) 1997 Elsevier Science Inc.