An inhibitor of c-jun aminoterminal kinase (SP600125) represses c-Jun activation, DNA-binding and PMA-inducible 92-kDa type IV collagenase expression.
The 92-kDa type IV collagenase (MMP-9) contributes to tumor invasion and metastases and strategies to down-regulate its expression could ultimately be of clinical utility. Although the expression of this collagenase is regulated by numerous growth factors, the signaling pathways that transduce these signals are fewer in number and therefore represent pharmacological targets. In this regard, we previously reported that MMP-9 expression was regulated by the c-jun amino terminal kinase (JNK) signaling cascade. Therefore, we undertook a study to determine the efficacy of a novel compound (SP600125), which binds to the ATP binding site of all known JNKs, in repressing MMP-9 expression. In OVCAR-3 cells, SP600125 inhibited the PMA-dependent secretion of MMP-9 in a time-dependent manner and over a dose range that blocked c-Jun phosphorylation and AP-1 binding. SP600125 repressed the activity of a PMA-stimulated MMP-9 promoter-driven luciferase reporter, suggesting that diminished secretion of this collagenase reflected reduced transcription. Further, the activity of a GAL4-driven reporter in PMA-treated cells, co-transfected with an expression construct encoding the trans-activation domain of c-Jun fused to the DNA binding domain of GAL4, was repressed by SP600125. These findings indicate the efficacy of SP600125 in inhibiting c-Jun activation, DNA-binding and the PMA-dependent induction of MMP-9 expression.
Shin
M
M
MD Anderson Cancer Center, Department of Cancer Biology, Box 179, 1515 Holcombe Blvd., Houston, TX 77030, USA.
Yan
C
C
Boyd
D
D
D000873:Anthracenes / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D016758:Genes, jun / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D011401:Promoter Regions, Genetic; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000873:Anthracenes; D014157:Transcription Factors; C432165:pyrazolanthrone; D004247:DNA; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9; D013755:Tetradecanoylphorbol Acetate