title: Mesalamine modulates intercellular adhesion through inhibition of p-21 activated kinase-1.
abstract: 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 APC(min) 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 APC(min) 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.
authors.affiliation: Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology and Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Vienna, Austria.
authors.forename: Vineeta
authors.initials: V
authors.lastname: Khare
authors.forename: Alex
authors.initials: A
authors.lastname: Lyakhovich
authors.forename: Kyle
authors.initials: K
authors.lastname: Dammann
authors.forename: Michaela
authors.initials: M
authors.lastname: Lang
authors.forename: Melanie
authors.initials: M
authors.lastname: Borgmann
authors.forename: Boris
authors.initials: B
authors.lastname: Tichy
authors.forename: Sarka
authors.initials: S
authors.lastname: Pospisilova
authors.forename: Gloria
authors.initials: G
authors.lastname: Luciani
authors.forename: Christoph
authors.initials: C
authors.lastname: Campregher
authors.forename: Rayko
authors.initials: R
authors.lastname: Evstatiev
authors.forename: Maren
authors.initials: M
authors.lastname: Pflueger
authors.forename: Harald
authors.initials: H
authors.lastname: Hundsberger
authors.forename: Christoph
authors.initials: C
authors.lastname: Gasche
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D016588:Anticarcinogenic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007417:Intestinal Polyps / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D019804:Mesalamine / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D016588:Anticarcinogenic Agents; D015820:Cadherins; C495268:Ctnnb1 protein, rat; D009363:Neoplasm Proteins; D051176:beta Catenin; D019804:Mesalamine; C515903:PAK1 protein, human; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases