Growth suppression of human ovarian cancer cells by adenovirus-mediated transfer of the PTEN gene.
A tumor suppressor gene on chromosome 10q23, PTEN, encodes a phosphatidylinositol phosphatase that antagonizes activation of the phosphatidylinositol 3'-kinase-mediated pathway involved in cell growth. A gene encoding the catalytic subunit of phosphatidylinositol 3'-kinase (PIK3CA) is frequently activated in ovarian cancers; therefore, overexpression of the PTEN product through gene transfer might be an effective strategy for treating ovarian cancers. To test the potential for this type of gene therapy, we constructed a recombinant adenovirus encoding wild-type PTEN and examined its effects on nine cell lines derived from human ovarian carcinomas. Transduction of the PTEN gene significantly inhibited growth of six of these cell lines compared with infection with virus alone, and the degree of inhibition correlated with the efficiency of gene transfer as determined by beta-galactosidase assay. Results of flow cytometry suggested that the observed effects were mediated by two mechanisms, apoptosis and/or arrest in the G1 phase of the cell cycle, and that high adenoviral transduction efficiency of cells was associated with induction of apoptosis. We also found that the level of transcription of Integrin alpha(v) in ovarian cancer cells correlated with the efficiency of transduction (P = 0.014) and with the degree of growth inhibition after PTEN gene transfer (P = 0.009). These findings carry significant implications for adenovirus vector-based PTEN gene therapies for ovarian cancers.
Minaguchi
T
T
Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Japan.
Mori
T
T
Kanamori
Y
Y
Matsushima
M
M
Yoshikawa
H
H
Taketani
Y
Y
Nakamura
Y
Y
D000256:Adenoviridae / Q000235:genetics; D015703:Antigens, CD / Q000096:biosynthesis; D017209:Apoptosis; D002455:Cell Division / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D039564:Integrin alphaV; D016023:Integrins / Q000096:biosynthesis; D010051:Ovarian Neoplasms / Q000628:therapy*; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
D015703:Antigens, CD; D039564:Integrin alphaV; D016023:Integrins; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human