Growth inhibition of non-small cell lung cancer cells by AP-1 blockade using a cJun dominant-negative mutant.
cJun, a major constituent of AP-1 transcription factor transducing multiple mitogen growth signals, is frequently overexpressed in non-small cell lung cancers (NSCLCs). The purpose of this study is to determine the effects of AP-1 blockade on the growth of NSCLC cells using a cJun dominant-negative mutant, TAM67. Transiently transfected TAM67 inhibited AP-1 transcriptional activity in NSCLC cell lines, NCI-H1299 (H1299), A549 and NCI-H520 (H520). The colony-forming efficiency of H1299 and A549 was reduced by TAM67, while that of H520 was not. To elucidate the effects of TAM67 on the growth of H1299, we established H1299 clone cells that expressed TAM67 under the control of a doxycycline-inducible promoter. In the H1299 clone cells, the induced TAM67 inhibited anchorage-dependent growth by promoting G1 cell-cycle block, but not by apoptosis. The induced TAM67 decreased the expression of a cell-cycle regulatory protein, cyclin A. TAM67 also inhibited anchorage-independent growth of these cells. Furthermore, TAM67 reduced growth of established xenograft tumours from these cells in nude mice. These results suggest that AP-1 plays an essential role in the growth of at least some of NSCLC cells.
Shimizu
Y
Y
Department of Medical Oncology, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan.
Kinoshita
I
I
Kikuchi
J
J
Yamazaki
K
K
Nishimura
M
M
Birrer
M J
MJ
Dosaka-Akita
H
H
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000628:therapy*; D004247:DNA / Q000378:metabolism; D005260:Female; D016193:G1 Phase; D015316:Genetic Therapy; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D014183:Transplantation, Heterologous
D010446:Peptide Fragments; D016755:Proto-Oncogene Proteins c-jun; C439528:TAM67 peptide; D018808:Transcription Factor AP-1; D004247:DNA