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.
AuthorsJ Westermarck, S Li, P Jaakkola, T Kallunki, R Grénman, V M Kähäri
JournalCancer research (Cancer Res) Vol. 60 Issue 24 Pg. 7156-62 (Dec 15 2000) ISSN: 0008-5472 [Print] United States
PMID11156425 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • ATF2 protein, human
  • Activating Transcription Factor 2
  • Atf2 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Recombinant Proteins
  • Transcription Factors
  • RNA
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Collagenases
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • Mmp13 protein, mouse
  • collagenase 1
  • Matrix Metalloproteinase 1
  • Activating Transcription Factor 2
  • Animals
  • Blotting, Northern
  • Carcinoma, Squamous Cell (enzymology)
  • Cells, Cultured
  • Collagenases (metabolism)
  • Cyclic AMP Response Element-Binding Protein (metabolism)
  • Enzyme Activation
  • Fibroblasts (enzymology)
  • Head and Neck Neoplasms (metabolism)
  • Humans
  • Infant, Newborn
  • Laryngeal Neoplasms (enzymology)
  • Matrix Metalloproteinase 1 (metabolism)
  • Matrix Metalloproteinase 13
  • Mice
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinases (metabolism)
  • Mouth Neoplasms (enzymology)
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Proteins c-fos (metabolism)
  • Proto-Oncogene Proteins c-jun (metabolism)
  • RNA (metabolism)
  • Recombinant Proteins (metabolism)
  • Time Factors
  • Transcription Factors (metabolism)
  • Transcription, Genetic
  • Transfection
  • Tumor Cells, Cultured
  • p38 Mitogen-Activated Protein Kinases

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