title: 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.
authors.affiliation: Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Seaho
authors.initials: S
authors.lastname: Kim
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Emilio P
authors.initials: EP
authors.lastname: Mottillo
authors.forename: Anjum
authors.initials: A
authors.lastname: Sohail
authors.forename: Yoon-Ah
authors.initials: YA
authors.lastname: Ham
authors.forename: M Katie
authors.initials: MK
authors.lastname: Conley-Lacomb
authors.forename: Chong Jai
authors.initials: CJ
authors.lastname: Kim
authors.forename: Guri
authors.initials: G
authors.lastname: Tzivion
authors.forename: Hyeong-Reh Choi
authors.initials: HR
authors.lastname: Kim
authors.forename: Shihua
authors.initials: S
authors.lastname: Wang
authors.forename: Yong Q
authors.initials: YQ
authors.lastname: Chen
authors.forename: Rafael
authors.initials: R
authors.lastname: Fridman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D018093:Gelatinases / Q000378:metabolism; D020869:Gene Expression Profiling; D005838:Genotype; D006031:Glycosylation; D006801:Humans; D015151:Immunoblotting; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D004792:Enzyme Precursors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D018093:Gelatinases; C069860:progelatinase; D053511:Matrix Metalloproteinase 14; D020123:Sirolimus