Induction of cell proliferation arrest and apoptosis in hepatoma cells through adenoviral-mediated transfer of p53 gene.
OBJECTIVE
Loss of p53 function is common in hepatocellular carcinoma and is associated with an extremely poor prognosis. The aim of the study was to evaluate the biologic effect of adenoviral-mediated gene transfer of wild-type p53 gene in four hepatoma cell lines with different p53 genetic makeup.


METHODS
Recombinant adenovirus expressing wild-type p53 was used. Recombinant adenoviruses with either an empty expression cassette or expressing beta-galactosidase gene served as controls.


RESULTS
High-level expression of wild-type p53 was achieved with adenoviral-mediated gene transfer. The expressed p53 protein showed nuclear localization and its expression was associated with an induction of p21 and bax expression. Expression of the p53 gene was associated with inhibition of tumor cell proliferation and induction of apoptosis. Expression of p53 was also associated with an upregulation of CD95 (Apo-1/Fas) gene expression, which may predispose the tumor cells to undergo apoptosis induced by the Fas Ligand/Fas cytolytic pathway. An additional anti-tumor effect, in terms of allowing the replication-defective adenovirus to replicate, was observed in hepatoma cells with homozygous deletion of p53 genes and to a lesser extent, hepatoma cells with mutated p53 genes.


CONCLUSIONS
These data showed that adenoviral-mediated gene transfer is effective in delivering p53 gene to tumor cells, and the multiple pathways involved in their antitumor activities.
Reiser
M
M
Medizinische Universitätsklinik, Knappschaftskrankenhaus Bochum, Germany.
Neumann
I
I
Schmiegel
W
W
Wu
P C
PC
Lau
J Y
JY
D000256:Adenoviridae; D017209:Apoptosis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology*; D002455:Cell Division / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D016158:Genes, p53; D005822:Genetic Vectors; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology*; D014407:Tumor Cells, Cultured