Confirmation of a linkage between H-Ras and MMP-13 expression as well as MMP-9 by chemical genomic approach.

As farnesylation of the Ras protein by farnesyl transferase is a critical step for the Ras functional activity, the farnesyl transferase inhibitor could affect H-Ras functions and the inhibitors such as arteminolide, SCH66336 and LB42908 completely inhibited Ras-farnesylation. However, they did not induce apoptosis of H-Ras-transformed cells with concentration for blocking H-Ras farnesylation. To determine the antitumor effects of the inhibitors, it was analyzed through the expression profile of genes, regulated by activated H-Ras or FTIs by using cDNA microarray. On the basis of the results, the relationship between H-Ras and MMPs expression was confirmed by RT-PCR, Western bolt, zymographic analysis and angiogenesis assay. Our results suggested that activation of MMP-13 as well as MMP-9 induced by H-Ras is involved in angiogenesis and with farnesyl transferase inhibitors, in part, exerts their anticancer effects. We confirmed that MMP-13 is a critical H-Ras target gene through chemical genomic approaches with farnesyl transferase inhibitors. 2005 Wiley-Liss, Inc.