Inhibition of MMP 14 potentiates the therapeutic effect of temozolomide and radiation in gliomas

Abstract

Metalloproteinases are membrane‐bound proteins that play a role in the cellular responses to antiglioma therapy. Previously, it has been shown that treatment of glioma cells with temozolomide (TMZ) and radiation (XRT) induces the expression of metalloproteinase 14 ( MMP 14). To investigate the role of MMP 14 in gliomagenesis, we used several chemical inhibitors which affect MMP 14 expression. Of all the inhibitors tested, we found that Marimastat not only inhibits the expression of MMP 14 in U87 and U251 glioma cells, but also induces cell cycle arrest. To determine the relationship between MMP 14 inhibition and alteration of the cell cycle, we used an RNA i technique. Genetic knockdown of MMP 14 in U87 and U251 glioma cells induced G 2 /M arrest and decreased proliferation. Mechanistically, we show that TMZ and XRT regulated expression of MMP 14 in clinical samples and in vitro models through downregulation of micro RNA 374. In vivo genetic knockdown of MMP 14 significantly decreased tumor growth of glioma xenografts and improved survival of glioma‐bearing mice. Moreover, the combination of MMP 14 silencing with TMZ and XRT significantly improved the survival of glioma‐bearing mice compared to a single modality treatment group. Therefore, we show that the inhibition of MMP 14 sensitizes tumor cells to TMZ and XRT and could be used as a future strategy for antiglioma therapy.