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 a denoviruses coding for TIMP-1, TIMP-2, and TIMP-3 resulted in marked s ecretion of TIMP-1 and TIMP-2 to culture medium and accumulation of TI MP-3 to matrix. Overexpression of TIMP-3 inhibited invasion of SK-Mel- 5 and A2058 cells through reconstituted basement membrane (Matrigel) e ven more potently than TIMP-1 and TIMP-2. In addition, overproduction of TIMP-3 reduced attachment of melanoma cells to type I and IV collag en and fibronectin and resulted in apoptosis in both SK-Mel-5 and A205 8 cells. These results propose a novel role for TIMP-3 in regulation o f invasion and survival of malignant cells and suggest potential use f or TIMP-3 in adenovirus-mediated gene therapy of malignant melanoma.