Mesalamine modulates intercellular adhesion intercellularadhesion through inhibition of p-21 activated kinase-1
2013
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 beta-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 beta-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.
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