Simultaneous blockade of AP-1 and phosphatidylinositol 3-kinase pathway in non-small cell lung cancer cells.
c-Jun is a major constituent of AP-1 transcription factor that transduces multiple mitogen growth signals, and it is frequently overexpressed in non-small cell lung cancers (NSCLCs). Earlier, we showed that blocking AP-1 by the overexpression of a c-Jun dominant-negative mutant, TAM67, inhibited NSCLC cell growth. The phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathway is important in transformation, proliferation, survival and metastasis of NSCLC cells. In this study, we used NCI-H1299 Tet-on clone cells that express TAM67 under the control of inducible promoter to determine the effects of inhibition of AP-1 and PI3K on cell growth. The PI3K inhibitor, LY294002, produced a dose-dependent inhibition of growth in H1299 cells and that inhibition was enhanced by TAM67. TAM67 increased dephosphorylation of Akt induced by LY294002 and reduced the TPA response element DNA-binding of phosphorylated c-Jun. TAM67 increased G1 cell cycle blockade induced by LY294002, which was partially associated with cyclin A decrease and p27(Kip1) accumulation. Furthermore, TAM67 and LY294002 act, at least additively, to inhibit anchorage-independent growth of the H1299 cells. These results suggest that AP-1 and PI3K/Akt pathways play an essential role in the growth of some NSCLC cells.
Kikuchi
J
J
First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Kinoshita
I
I
Shimizu
Y
Y
Oizumi
S
S
Nishimura
M
M
Birrer
M J
MJ
Dosaka-Akita
H
H
D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D019925:Cyclin A / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D002867:Chromones; D019925:Cyclin A; D050760:Cyclin-Dependent Kinase Inhibitor p27; D009025:Morpholines; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; C439528:TAM67 peptide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one