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 in vitro, including cell proliferation, survival, transformation, and chemotaxis. PDGF functions as a "competence factor" to induce a set of early response genes expressed in G1 including p21WAF1/CIP1, a functional mediator of the tumor suppressor gene p53 in G1/S checkpoint. For PDGF-stimulated cells to progress beyond G1 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 G1/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 p28v-sis expression vector, which was previously shown to activate PDGF alpha- and beta- receptors. Although the basal level of p21WAF1/CIP1 expression and radiation-induced apoptosis were not detectable in control 125-IL cells as would be predicted in mutant p53-containing cells, activation of PDGF-signaling induced expression of p21WAF1/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.
Kim
H E
HE
Department of Radiation Oncology, Wayne State University School of Medicine, Detroit, MI 48202, USA.
Han
S J
SJ
Kasza
T
T
Han
R
R
Choi
H S
HS
Palmer
K C
KC
Kim
H R
HR
D017209:Apoptosis / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D016895:Culture Media, Serum-Free; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D016158:Genes, p53 / Q000235:genetics*; D005822:Genetic Vectors / Q000502:physiology; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D009154:Mutation; D020575:Oncogene Proteins v-sis; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000532:radiotherapy; D015682:Retroviridae Proteins, Oncogenic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology / Q000528:radiation effects*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C493956:CDKN1A protein, human; D016895:Culture Media, Serum-Free; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D020575:Oncogene Proteins v-sis; D010982:Platelet-Derived Growth Factor; D015682:Retroviridae Proteins, Oncogenic; D016159:Tumor Suppressor Protein p53