Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1
| Autor: | Michaela Lang, Šárka Pospíšilová, Christoph Gasche, Melanie Borgmann, Boris Tichy, Maren Pflueger, Vineeta Khare, Harald Hundsberger, Alex Lyakhovich, Rayko Evstatiev, Gloria Luciani, Christoph Campregher, Kyle Dammann |
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| Rok vydání: | 2013 |
| Předmět: |
Male
MAPK/ERK pathway Biochemistry Mice 0302 clinical medicine Mesalamine Wnt Signaling Pathway beta Catenin 0303 health sciences Cell adhesion molecule Anti-Inflammatory Agents Non-Steroidal Wnt signaling pathway Intestinal Polyps Adhesion Cadherins Intercellular adhesion molecule Neoplasm Proteins 3. Good health Cell biology surgical procedures operative 030220 oncology & carcinogenesis Colonic Neoplasms CRC colorectal cancer Female RNA Interference MAP Kinase Signaling System education Down-Regulation Biology Article 03 medical and health sciences Cell Line Tumor Animals Anticarcinogenic Agents Humans IBD inflammatory bowel diseases Cell adhesion 030304 developmental biology Pharmacology Cadherin Gene Expression Profiling Soluble cell adhesion molecules E-cadherin AJ adherens junction digestive system diseases UC ulcerative colitis p21-Activated Kinases Beta-catenin Cancer research PAK1 PAK1 p21 activated kinase 1 |
| Zdroj: | Biochemical Pharmacology |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/j.bcp.2012.10.026 |
| Popis: | Graphical abstract (a) PAK1 orchestrates mesalamine activity, (b) mesalamine inhibits PAK1; increases membranous E-cadherin and β-catenin; modulates cell adhesion Mesalamine (5-ASA) is widely used for the treatment of ulcerative colitis, a remitting condition characterized by chronic inflammation of the colon. Knowledge about the molecular and cellular targets of 5-ASA is limited and a clear understanding of its activity in intestinal homeostasis and interference with neoplastic progression is lacking. We sought to identify molecular pathways interfered by 5-ASA, using CRC cell lines with different genetic background. Microarray was performed for gene expression profile of 5-ASA-treated and untreated cells (HCT116 and HT29). Filtering and analysis of data identified three oncogenic pathways interfered by 5-ASA: MAPK/ERK pathway, cell adhesion and β-catenin/Wnt signaling. PAK1 emerged as a consensus target of 5-ASA, orchestrating these pathways. We further investigated the effect of 5-ASA on cell adhesion. 5-ASA increased cell adhesion which was measured by cell adhesion assay and transcellular-resistance measurement. Moreover, 5-ASA treatment restored membranous expression of adhesion molecules E-cadherin and β-catenin. Role of PAK1 as a mediator of mesalamine activity was validated in vitro and in vivo. Inhibition of PAK1 by RNA interference also increased cell adhesion. PAK1 expression was elevated in APCmin polyps and 5-ASA treatment reduced its expression. Our data demonstrates novel pharmacological mechanism of mesalamine in modulation of cell adhesion and role of PAK1 in APCmin polyposis. We propose that inhibition of PAK1 expression by 5-ASA can impede with neoplastic progression in colorectal carcinogenesis. The mechanism of PAK1 inhibition and induction of membranous translocation of adhesion proteins by 5-ASA might be independent of its known anti-inflammatory action. |
| Databáze: | OpenAIRE |
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