title: PHLPP negatively regulates cell motility through inhibition of Akt activity and integrin expression in pancreatic cancer cells.
abstract: Pancreatic adenocarcinoma is currently the fourth leading cause for cancer-related mortality. Malignant progression of pancreatic cancer depends not only on rapid proliferation of tumor cells but also on increased cell motility. In this study, we showed that increased PHLPP expression significantly reduced the rate of migration in pancreatic ductal adenocarcinoma (PDAC) cells whereas knockdown of PHLPP had the opposite effect. In addition, cell motility at the individual cell level was negatively regulated by PHLPP as determined using time-lapse imaging. Interestingly, the expression of β1 and β4 integrin proteins were decreased in PHLPP overexpressing cells and increased in PHLPP knockdown cells whereas the mRNA levels of integrin were not altered by changes in PHLPP expression. In determining the molecular mechanism underlying PHLPP-mediated regulation of integrin expression, we found that inhibition of lysosome activity rescued integrin expression in PHLPP overexpressing cells, thus suggesting that PHLPP negatively controls cell motility by inhibiting Akt activity to promote lysosome-dependent degradation of integrins. Functionally, the increased cell migration observed in PHLPP knockdown cells was effectively blocked by the neutralizing antibodies against β1 or β4 integrin. Taken together, our study identified a tumor suppressor role of PHLPP in suppressing cell motility by negatively regulating integrin expression in pancreatic cancer cells.
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.
authors.forename: Alena J
authors.initials: AJ
authors.lastname: Smith
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: Yang-An
authors.initials: YA
authors.lastname: Wen
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.
authors.forename: Payton D
authors.initials: PD
authors.lastname: Stevens
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: Jingpeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: Chi
authors.initials: C
authors.lastname: Wang
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.
authors.forename: Tianyan
authors.initials: T
authors.lastname: Gao
mesh_terms: D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D016023:Integrins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D051057:Proto-Oncogene Proteins c-akt; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases
keywords: PHLPP; cell migration; integrin; pancreatic cancer; tumor suppressor