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: Xuejian Wang, Lihong Shi, Yilin Deng, Meihua Qu, Shumei Mao, Liyan Xu, Wenfang Xu, Chunyan Fang
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 768 Pg. 116-22 (Dec 05 2015) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 26526349 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier B.V.

Chemical References

• Carrier Proteins
• HSP27 Heat-Shock Proteins
• Microfilament Proteins
• Protease Inhibitors
• RNA, Small Interfering
• fascin
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• p38 Mitogen-Activated Protein Kinases
• Leucyl Aminopeptidase
• Matrix Metalloproteinase 2
• Matrix Metalloproteinase 9
• Leucine
• ubenimex

Topics

• Carrier Proteins (metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Down-Regulation (drug effects)
• Female
• Gene Knockdown Techniques
• HSP27 Heat-Shock Proteins (metabolism)
• Humans
• Leucine (analogs & derivatives, pharmacology)
• Leucyl Aminopeptidase (antagonists & inhibitors, deficiency, genetics)
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Microfilament Proteins (metabolism)
• Neoplasm Invasiveness
• Ovarian Neoplasms (pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protease Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering (genetics)
• Signal Transduction (drug effects)
• Up-Regulation (drug effects)
• p38 Mitogen-Activated Protein Kinases (metabolism)