Suppression of matrix metalloproteinase-2 gene expression and invasion in human glioma cells by MMAC/PTEN

Human gliomas are highly invasive, and remain to be a major obstacle for an y effective therapeutic remedy. Among many other factors, gliomas express e levated levels of matrix metalloproteinases (MMPs), which have been implica ted to play an important role in tumor invasion as well as neovascularizati on. The tumor suppressor gene mutated in multiple advanced cancers/phosphat ase and tensin homologue (MMAC/PTEN) has been shown to inhibit cell migrati on, spreading, and focal adhesion. In this study, we determined whether MMA C/PTEN inhibits tumor invasion by modulating MMP-2 activity. Our results sh owed that reintroduction of the MMAC/PTEN gene into human glioma U251 and U 87 cells modified their phenotype and growth characteristics. The ability o f MMAC/PTEN to induce anoikis in U251 cells was accompanied by a significan t inhibition of in vitro invasion (70%). Expression of MMAC/PTEN in U251 an d U87 cells inhibited MMP-2 enzymatic activity as determined by zymography. Furthermore, MMAC/PTEN expression strongly decreased MMP-2 mRNA levels, wh ich correlated well with the inhibition of invasion capacity in these cells . Concomitant with MMP-2 expression and activity, MMP-2 promoter activity w as also reduced in MMAC/PTEN expressing cells. Our observations suggest tha t MMAC/PTEN inhibits tumor cell invasion in part by regulating MMP-2 gene t ranscription and thereby its enzymatic activity. Further characterization o f this regulation will facilitate the development of MMAC/PTEN based gene t herapy for gliomas.