Adenoviral delivery of p53 gene suppresses expression of collagenase-3 (MMP-13) in squamous carcinoma cells.
Squamous cell carcinomas (SCCs) of the head and neck are characterized by high tendency to invade locally and metastasize to lymph nodes. SCC cells express several matrix metalloproteinases (MMPs) and they often harbor mutations in p53 tumor suppressor gene. Collagenase-3 (MMP-13) is specifically expressed by tumor cells of SCCs and it apparently plays an important role in their invasion and metastasis. We used adenoviral gene delivery to examine the effect of wild-type p53 on MMP-13 expression in four head and neck SCC cell lines with mutated p53. Adenoviral delivery of p53 resulted in potent inhibition in production of proMMP-13 (by 71 to 92%) and collagenase-1 (MMP-1) (by 27 to 93%) by all cell lines in 24 h, whereas production of gelatinase-A (MMP-2) and gelatinase-B (MMP-9) was not altered. Adenoviral expression of p53 also suppressed invasion of SCC cells through Matrigel by 35%. Expression of cyclin-dependent kinase inhibitor p21(Waf1/Cip1) was induced 24 h after p53 gene delivery in all SCC cell lines, except one, which lacked detectable p21(Waf1/Cip1) expression. Number of viable cells was not altered and no apoptotic cells were seen 24 h after p53 delivery. These results show, that wild-type p53 potently inhibits expression of MMP-13 and MMP-1 by SCC cells independently of its pro-apoptotic effect. Together these results indicate, that p53 exerts a bi-phasic tumor suppressor effect on SCC cells: inhibition of cell invasion followed by induction of programmed cell death.
Ala-aho
Risto
R
Centre for Biotechnology, University of Turku, Tykistökatu 6B, FIN-20520 Turku, Finland.
Grénman
Reidar
R
Seth
Prem
P
Kähäri
Veli-Matti
VM
D000256:Adenoviridae / Q000235:genetics*; D017209:Apoptosis; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism; D002470:Cell Survival; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000096:biosynthesis* / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D004338:Drug Combinations; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D007797:Laminin / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis / Q000235:genetics; D053509:Matrix Metalloproteinase 13; D009361:Neoplasm Invasiveness; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D019076:Transgenes / Q000235:genetics*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C059485:matrigel; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003094:Collagen; D017364:Collagenases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020781:Matrix Metalloproteinase 1