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Adenovirus-mediated Gene Delivery of Tissue Inhibitor of Metalloproteinases-3 Inhibits Invasion and Induces Apoptosis in Melanoma Cells¹

Department of Dermatology, Turku University Central Hospital, and MediCity Research Laboratory and Department of Medical Biochemistry, University of Turku, FIN-20520 Turku, Finland [M. A., V-M. K.]; and Bristol Heart Institute, Bristol Royal Infirmary, Bristol, BS2 8HW, United Kingdom [A. H. B.]

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.

¹ Supported by grants from the Academy of Finland, Sigrid Jusélius Foundation, the Cancer Foundation of Finland, Turku University Central Hospital, and Medical Research Council of Great Britain. M. A. is a student in Turku Graduate School in Biomedical Sciences.

² To whom requests for reprints should be addressed, at University of Turku, MediCity Research Laboratory, Tykistökatu 6, FIN-20520 Turku, Finland. Phone: 358-2-3337025; Fax: 358-2-3337000; E-mail: veli-matti.kahari@utu.fi.

Received 3/10/98. Accepted 4/16/98.

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