Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells.
We have used adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinase (TIMP)-1, -2, and -3 to examine their effect on the invasion capacity of metastatic melanoma cell lines SK-Mel-5 and A2058. Infection of melanoma cells with recombinant replication-deficient adenoviruses coding for TIMP-1, TIMP-2, and TIMP-3 resulted in marked secretion of TIMP-1 and TIMP-2 to culture medium and accumulation of TIMP-3 to matrix. Overexpression of TIMP-3 inhibited invasion of SK-Mel-5 and A2058 cells through reconstituted basement membrane (Matrigel) even more potently than TIMP-1 and TIMP-2. In addition, overproduction of TIMP-3 reduced attachment of melanoma cells to type I and IV collagen and fibronectin and resulted in apoptosis in both SK-Mel-5 and A2058 cells. These results propose a novel role for TIMP-3 in regulation of invasion and survival of malignant cells and suggest potential use for TIMP-3 in adenovirus-mediated gene therapy of malignant melanoma.
Ahonen
M
M
Department of Dermatology, Turku University Central Hospital, and MediCity Research Laboratory, University of Turku, Finland.
Baker
A H
AH
Kähäri
V M
VM
D000256:Adenoviridae; D017209:Apoptosis; D002448:Cell Adhesion; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D009361:Neoplasm Invasiveness; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000096:biosynthesis / Q000235:genetics*; D014407:Tumor Cells, Cultured
D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D019716:Tissue Inhibitor of Metalloproteinase-2