TY - JOUR
T1 - Adenovirus-mediated p14(ARF) gene transfer in human mesothelioma cells
AU - Yang, Cheng Ta
AU - You, Liang
AU - Yeh, Che Chung
AU - Chang, John Wen Cheng
AU - Zhang, Fen
AU - McCormick, Frank
AU - Jablons, David M.
PY - 2000/4/19
Y1 - 2000/4/19
N2 - Background: The p14(ARF) protein encoded by the INK4a/ARF locus promotes degradation of the MDM2 protein and thus prevents the MDM2-mediated inhibition of p53. Homozygous deletion of the INK4a/ARF locus is common in human mesothelioma and may result in the loss of p14(ARF) and the inactivation of p53. We designed this study to evaluate the biologic and potential therapeutic roles of p14(ARF) expression in mesothelioma cells. Methods and Results: We constructed Adp14, an adenoviral vector carrying human p14(ARF) complementary DNA, and used it to transfect human mesothelioma cell lines H28, H513, H2052, and MSTO211H. Overexpression of p14(ARF) led to increased amounts of p53 and the p21(WAF) proteins and dephosphorylation of the retinoblastoma protein. The growth rate of mesothelioma cells was inhibited markedly by infection with Adp14 compared with mock infection or infection with a control adenovirus vector, AdCtrl. Overexpression of p14(ARF) induced G1-phase cell cycle arrest and apoptotic cell death. Cytotoxicity assays showed that Adp14 had a statistically significantly (P = .002) greater effect on colon cancer (HCT116) cell lines containing two copies of the wild-type p53 gene than on p53-null cells, suggesting that functional p53 is a critical determinant of p14(ARF)-mediated cytotoxicity. Conclusions: The transfection of p14(ARF) into mesothelioma cells led to the overexpression of p14(ARF), which resulted in G1-phase arrest and apoptotic cell death. These results suggest that this gene therapy-based approach may be of use in the treatment of mesothelioma.
AB - Background: The p14(ARF) protein encoded by the INK4a/ARF locus promotes degradation of the MDM2 protein and thus prevents the MDM2-mediated inhibition of p53. Homozygous deletion of the INK4a/ARF locus is common in human mesothelioma and may result in the loss of p14(ARF) and the inactivation of p53. We designed this study to evaluate the biologic and potential therapeutic roles of p14(ARF) expression in mesothelioma cells. Methods and Results: We constructed Adp14, an adenoviral vector carrying human p14(ARF) complementary DNA, and used it to transfect human mesothelioma cell lines H28, H513, H2052, and MSTO211H. Overexpression of p14(ARF) led to increased amounts of p53 and the p21(WAF) proteins and dephosphorylation of the retinoblastoma protein. The growth rate of mesothelioma cells was inhibited markedly by infection with Adp14 compared with mock infection or infection with a control adenovirus vector, AdCtrl. Overexpression of p14(ARF) induced G1-phase cell cycle arrest and apoptotic cell death. Cytotoxicity assays showed that Adp14 had a statistically significantly (P = .002) greater effect on colon cancer (HCT116) cell lines containing two copies of the wild-type p53 gene than on p53-null cells, suggesting that functional p53 is a critical determinant of p14(ARF)-mediated cytotoxicity. Conclusions: The transfection of p14(ARF) into mesothelioma cells led to the overexpression of p14(ARF), which resulted in G1-phase arrest and apoptotic cell death. These results suggest that this gene therapy-based approach may be of use in the treatment of mesothelioma.
UR - http://www.scopus.com/inward/record.url?scp=0034685531&partnerID=8YFLogxK
U2 - 10.1093/jnci/92.8.636
DO - 10.1093/jnci/92.8.636
M3 - 文章
C2 - 10772681
AN - SCOPUS:0034685531
SN - 0027-8874
VL - 92
SP - 636
EP - 641
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 8
ER -
