期刊
ONCOGENE
卷 19, 期 48, 页码 5444-5452出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1203928
关键词
tumor invasion; matrix metalloproteinases; integrins; signal transduction; AP-1 transcription factor
Overexpression of Integrin Linked Kinase (ILK) in intestinal and mammary epithelial cells results in a highly invasive phenotype, associated with increased levels of expression of the matrix metalloproteinase MMP-9. This increase was at the transcriptional level as determined by MMP-9 promoter-CAT reporter assays. Mutations in the two AP-1 binding sites within the MMP-9 promoter completely inhibited the reporter activity. We have previously shown that ILK inhibits glycogen synthase kinase-3 (GSK-3) activity, Transient transfection of wild-type GSK-3 beta in ILK-overexpressing cells decreased MMP-9 promoter activity and AP-I activity, indicating that ILK can stimulate MMP-9 expression via GSK-3 beta and AP-1 transcription factor, A small molecule inhibitor of the ILK kinase reduced the in vitro invasiveness of ILK-overexpressing cells as well as the invasiveness of several human brain tumor cell lines. Furthermore, both MMP-9 promoter and AP-1 activities mere inhibited by the ILK inhibitor. Invasiveness of ILK-overexpressing cells was also reduced by inhibition of MMP-9. These data demonstrate that ILK can induce an invasive phenotype via AP-1-dependent upregulation of MMP-9.
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