CD40L induces matrix-metalloproteinase-9 but not tissue inhibitor of metalloproteinases-1 in cervical carcinoma cells: imbalance between NF-kappaB and STAT3 activation.
Matrix-metalloproteinases (MMPs) are essentially required for tumor cell invasion and metastasis. Production of precursor enzymes is regulated on transcriptional level, while activation of the pro-enzymes is tightly controlled by posttranscriptional mechanisms. The enzyme activity can be blocked by specific tissue inhibitors of MMPs (TIMPs). In cervical carcinomas strong up-regulation of the type IV collagenase MMP-9 had been demonstrated. We show that activation of CD40, a receptor highly expressed on cervical carcinomas, induces MMP-9 in cervical carcinoma cells, whereas TIMP-1 production inhibiting MMP-9 activity was not affected. This gene induction pattern corresponded to the differential activation of the transcription factor nuclear factor kappaB (NF-kappaB) regulating MMP-9, but not signal transducer and activator of transcription 3 (STAT3), which is involved in TIMP-1 gene regulation. Transient expression of the CD40-inducible NF-kappaB subunit p65 was sufficient for MMP-9 induction. Agents that suppressed CD40-mediated NF-kappaB activation also reduced MMP-9 induction, further supporting an important role of NF-kappaB in CD40-mediated MMP-9 induction. Our data suggest that CD40 expression in carcinoma cells might convert a CD40L-dependent immunological defense signal into a tumor-promoting signal. Selective CD40-mediated signaling through NF-kappaB but not STAT3 correlates to a shift of the balance between MMP-9 and TIMP-1 toward the protease.
Smola-Hess
S
S
Institute of Virology, University of Cologne, Fürst-Pückler-Str. 56, Cologne, 50935, Germany. s.hess@uni-koeln.de
Schnitzler
R
R
Hadaschik
D
D
Smola
H
H
Mauch
C
C
Krieg
T
T
Pfister
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D023201:CD40 Ligand / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles; D009930:Organic Chemicals; D011480:Protease Inhibitors / Q000378:metabolism; D021122:Protein Subunits; D050796:STAT3 Transcription Factor; D013450:Sulfones; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000378:metabolism*
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D009570:Nitriles; D009930:Organic Chemicals; D011480:Protease Inhibitors; D021122:Protein Subunits; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013450:Sulfones; D019714:Tissue Inhibitor of Metalloproteinases; D015534:Trans-Activators; D023201:CD40 Ligand; D020780:Matrix Metalloproteinase 9