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.
Lee
Su-Kyung
SK
Korea Research Institute of Bioscience and Biotechnology, Yoosunggu, Taejon 305-600, Korea.
Kim
Jung Min
JM
Lee
Mi-Young
MY
Son
Kwang-Hee
KH
Yeom
Young Il
YI
Kim
Cheol-Hee
CH
Shin
Youseung
Y
Koh
Jong Sung
JS
Han
Dong Cho
DC
Kwon
Byoung-Mog
BM
D000818:Animals; D015153:Blotting, Western; D017364:Collagenases / Q000096:biosynthesis*; D042783:Endothelial Cells; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005347:Fibroblasts; D020869:Gene Expression Profiling; D011905:Genes, ras; D023281:Genomics; D053509:Matrix Metalloproteinase 13; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D009389:Neovascularization, Pathologic; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D051231:Farnesyltranstransferase; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; C507083:Mmp13 protein, rat; D020780:Matrix Metalloproteinase 9