Posttranslational Regulation of Membrane Type 1-Matrix Metalloproteinase (MT1-MMP) in Mouse PTEN Null Prostate Cancer Cells: Enhanced Surface Expression and Differential O-Glycosylation of MT1-MMP

Abstract Membrane type 1 (MT1)-matrix metalloproteinase (MT1-MMP) is a membrane-tethered MMP that has been shown to play a key role in promoting cancer cell invasion. MT1-MMP is highly expressed in bone metastasis of prostate cancer (PC) patients and promotes intraosseous tumor growth of PC cells in mice. The majority of metastatic prostate cancers harbor loss-of-function mutations or deletions of the tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome ten). However, the role of PTEN inactivation in MT1-MMP expression in PC cells has not been examined. In this study, prostate epithelial cell lines derived from mice that are either heterozygous ( PTEN +/- ) or homozygous ( PTEN −/− ) for PTEN deletion or harboring a wild-type PTEN ( PTEN +/+ ) were used to investigate the expression of MT1-MMP. We found that biallelic loss of PTEN is associated with posttranslational regulation of MT1-MMP protein in mouse PC cells. PTEN −/− PC cells display higher levels of MT1-MMP at the cell surface when compared to PTEN +/+ and PTEN +/ − cells and consequently exhibited enhanced migratory and collagen-invasive activities. MT1-MMP displayed by PTEN −/− cells is differentially O -glycosylated and exhibits a slow rate of turnover. MT1-MMP expression in PTEN −/− cells is under control of the PI3K/AKT signaling pathway, as determined using pharmacological inhibitors. Interestingly, rapamycin, an mTOR inhibitor, upregulates MT1-MMP expression in PTEN +/+ cells via PI3K activity. Collectively, these data in a mouse prostate cell system uncover for the first time a novel and complex relationship between PTEN loss-mediated PI3K/AKT activation and posttranslational regulation of MT1-MMP, which may play a role in PC progression.