title: Inhibition of leucine aminopeptidase 3 suppresses invasion of ovarian cancer cells through down-regulation of fascin and MMP-2/9.
abstract: Leucine aminopeptidase 3 (LAP3) is a cell surface aminopeptidase that catalyzes the hydrolysis of leucine residues from the amino termini of protein or peptide substrates. The over-expression of LAP3 correlates with prognosis and malignant development of several human cell carcinomas. However, the molecular mechanism remains unknown. In this study, we used ES-2 ovarian cancer cell line as a model system to explore the role of LAP3 in regulation of cancer cell invasion by employing a natural LAP3 inhibitor bestatin and LAP3 siRNA. Bestatin inhibited tumor cell migration and invasion in a dose-dependent manner. More interestingly, bestatin down-regulated expression of fascin protein and inhibited activity of fascin promoter luciferase reporter. Both proteome profiler array and Western blot assay showed that bestatin up-regulated the phosphorylation of Hsp27. Furthermore, LAP3 siRNA could up-regulate the phosphorylation of Hsp27 and down-regulate the expression of fascin. Meanwhile, LAP3 siRNA could also down-regulate the phosphorylation of Akt and the expression of MMP-2/9. Taken together, LAP3 could affect the expression of fascin and MMP-2/9 and may act as a potential anti-metastasis therapeutic target.
authors.affiliation: Key Laboratory of Applied Pharmacology in Universities of Sh andong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China.
authors.forename: Xuejian
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Applied Pharmacology in Universities of Sh andong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Shi
authors.affiliation: Tender Office, Wei Fang People's Hospital, Weifang 261041, Shandong, China.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Key Laboratory of Applied Pharmacology in Universities of Sh andong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China.
authors.forename: Meihua
authors.initials: M
authors.lastname: Qu
authors.affiliation: Key Laboratory of Applied Pharmacology in Universities of Sh andong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China.
authors.forename: Shumei
authors.initials: S
authors.lastname: Mao
authors.affiliation: Institute of Oncologic Pathology, The Key Immunopathology Laboratory of Guangdong Province, Shantou University Medical College, Shantou 515041, Guangdong, China.
authors.forename: Liyan
authors.initials: L
authors.lastname: Xu
authors.affiliation: Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Xu
authors.affiliation: Key Laboratory of Applied Pharmacology in Universities of Sh andong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China. Electronic address: chunyanfang@163.com.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Fang
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D055785:Gene Knockdown Techniques; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D007931:Leucyl Aminopeptidase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D055551:HSP27 Heat-Shock Proteins; D008840:Microfilament Proteins; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; C020324:fascin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D007931:Leucyl Aminopeptidase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D007930:Leucine; C012211:ubenimex
keywords: Fascin; Invasion; LAP3; MMPs; Signaling transduction