CD40L induces matrix-metalloproteinase-9 but not tissue inhibitor of metalloproteinases-1 in cervical carcinoma cells: imbalance between NF-kappaB and STAT3 activation

• Published in: Experimental cell research Vol. 267; no. 2; pp. 205 - 215
• Main Authors: Smola-Hess, S, Schnitzler, R, Hadaschik, D, Smola, H, Mauch, C, Krieg, T, Pfister, H
• Format: Journal Article
• Language: English
• Published: United States 15.07.2001
• Subjects: Animals; Antineoplastic Agents - pharmacology; CD40 Ligand - metabolism; DNA-Binding Proteins - metabolism; Female; Gene Expression Regulation, Neoplastic; Humans; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; NF-kappa B - antagonists & inhibitors; NF-kappa B - genetics; NF-kappa B - metabolism; Nitriles; Organic Chemicals; Protease Inhibitors - metabolism; Protein Subunits; STAT3 Transcription Factor; Sulfones; Tissue Inhibitor of Metalloproteinases - genetics; Tissue Inhibitor of Metalloproteinases - metabolism; Trans-Activators - metabolism; Transcriptional Activation; Tumor Cells, Cultured; Uterine Cervical Neoplasms - genetics; Uterine Cervical Neoplasms - metabolism
• ISSN: 0014-4827

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.