Dominant-negative mutant of c-Jun gene transfer: a novel therapeutic strategy for colorectal cancer.
Activator protein-1 (AP-1), a transcription factor, is activated through many oncogenic signals. However, its biological role in colorectal cancer has not been fully elucidated. To investigate the role of AP-1 in colorectal cancer, we constructed an adenovirus-expressing TAM67, a dominant-negative mutant of c-Jun lacking the transactivation domain of wild c-Jun (DN-c-Jun), to inhibit endogenous AP-1. AP-1 DNA-binding activity was increased in colon cancer cells (HT-29 cells) by serum stimulation, followed by an increase in both [(3)H]thymidine incorporation and cell number. Transfection of Ad-DN-c-Jun to HT-29 cells significantly inhibited serum-induced cell proliferation in vitro. As shown by flow cytometric analysis, DN-c-Jun significantly inhibited entrance into S phase after serum stimulation, thereby leading to G(1) arrest. In vivo transfection of Ad-DN-c-Jun into xenografted HT-29 cell tumors in nude mice significantly decreased tumor volume on day 21 after treatment. A change was associated with decrease in Ki-67 labeling index. These observations together showed that AP-1 is a critical modulator for proliferation and cell cycle of HT-29 cells. We obtained the first evidence that DN-c-Jun gene transfer exerted a significant antitumor effect on colon cancer both in vitro and in vivo. DN-c-Jun gene transfer may be a new candidate for treatment of colorectal cancer.
Suto
R
R
Department of Gastroenterology, Graduate School of Medicine, Osaka City University Medical School, Abeno-ku, Osaka, Japan.
Tominaga
K
K
Mizuguchi
H
H
Sasaki
E
E
Higuchi
K
K
Kim
S
S
Iwao
H
H
Arakawa
T
T
D000818:Animals; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000628:therapy*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D019073:HT29 Cells; D006801:Humans; D015552:Injections, Intralesional; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014162:Transfection / Q000379:methods
D004268:DNA-Binding Proteins; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1