Activation of fibroblast collagenase-1 expression by tumor cells of squamous cell carcinomas is mediated by p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase-2.
Collagenase-1 [matrix metalloproteinase (MMP)-1] is expressed by stromal fibroblasts of various invasive malignant tumors. Here, we have examined the molecular mechanisms of tumor-induced expression of MMP-1 by stromal fibroblasts. Treatment of fibroblasts with conditioned media of tumor cells derived from squamous cell carcinomas (SCCs) of the oral cavity and larynx resulted in activation of fibroblast MMP-1 expression at the transcriptional level. The induction of MMP-1 expression correlates with activation of c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase and phosphorylation of c-Jun and activating transcription factor-2 (ATF-2) and is dependent on the activity of p38 mitogen-activated protein kinase. Furthermore, using fibroblasts derived from JNK2-/- mice, we show that JNK2 is required for induction of fibroblast collagenase-3 expression in response to conditioned SCC tumor cell medium. Together, these results provide evidence that stress-activated p38 and JNK pathways play a crucial role in paracrine regulation of collagenolytic capacity of stromal fibroblasts in SCCs and suggest JNK2 as a novel target for inhibition of MMP-1 expression and tumor invasion.
Westermarck
J
J
Turku Centre for Biotechnology, University of Turku, Finland. jukwes@utu.fi
Li
S
S
Jaakkola
P
P
Kallunki
T
T
Grénman
R
R
Kähäri
V M
VM
D051698:Activating Transcription Factor 2; D000818:Animals; D015152:Blotting, Northern; D002294:Carcinoma, Squamous Cell / Q000201:enzymology*; D002478:Cells, Cultured; D017364:Collagenases / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000201:enzymology*; D006258:Head and Neck Neoplasms / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D007822:Laryngeal Neoplasms / Q000201:enzymology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053509:Matrix Metalloproteinase 13; D051379:Mice; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000201:enzymology; D010641:Phenotype; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011994:Recombinant Proteins; D014157:Transcription Factors; D012313:RNA; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; C417249:collagenase 1; D020781:Matrix Metalloproteinase 1