Characterization of a Novel Tumor Suppressor Gene, mda-7, and its Ability to Induce Apoptosis

摘要

Subtraction hybridization identified melanoma differentiation associated gene-7 (mda-7) as a gene induced during terminal differentiation in human melanoma cells. Administration of mda-7 by means of a replication- incompetent adenovirus (Ad.mda-7) induces apoptosis selectively in diverse human cancer cells without inducing harmful effects in normal fibroblast or epithelial cells. The present studies investigated the mechanism underlying this differential apoptotic effect. Infection with Ad.mda-7 induced a family of growth arrest and DNA damage (GADD)-inducible genes in diverse cancer cell lines but not in their normal counterparts, which correlated with induction of apoptosis. Treatment with SB203580, a selective inhibitor of p38 MAPK, and infection with an adenovirus expressing a dominant negative inhibitor of p38 MAPK, effectively inhibited Ad.mda-7-induced apoptosis and GADD gene family induction. Ad.mda-7 infection resulted in phosphorylation of p38 MAPK in cancer cells but not in normal cells. Inhibition of GADD genes by an antisense approach effectively blocked Ad.mda-7-induced apoptosis. These results support the hypothesis that Ad.mda-7 mediates induction of the GADD family of genes by means of the p38 MAPK pathway, thereby resulting in the selective induction of apoptosis in cancer cells.