Prostaglandin E2-EP1 and EP2 receptor signaling promotes apical junctional complex disassembly of Caco-2 human colorectal cancer cells.
BACKGROUND
The apical junctional complex (AJC) is a dynamic structure responsible to maintain epithelial cell-cell adhesions and it plays important functions such as, polarity, mechanical integrity, and cell signaling. Alteration of this complex during pathological events leads to an impaired epithelial barrier by perturbation of the cell-cell adhesion system. Although clinical and experimental data indicate that prostaglandin E(2) (PGE2) plays a critical function in promoting cell motility and cancer progression, little is known concerning its role in AJC disassembly, an event that takes place at the beginning of colorectal tumorigenesis. Using Caco-2 cells, a cell line derived from human colorectal cancer, we investigated the effects of prostaglandin E(2) (PGE(2)) treatment on AJC assembly and function.


RESULTS
Exposition of Caco-2 cells to PGE(2) promoted differential alteration of AJC protein distribution, as evidenced by immunofluorescence and immunoblotting analysis and impairs the barrier function, as seen by a decrease in the transepithelial electric resistance and an increase in the permeability to ruthenium red marker. We demonstrated the involvement of EP1 and EP2 prostaglandin E(2) receptor subtypes in the modulation of the AJC disassembly caused by prostanoid. Furthermore, pharmacological inhibition of protein kinase-C, but not PKA and p38MAPK significantly prevented the PGE(2) effects on the AJC disassembly.


CONCLUSIONS
Our findings strongly suggest a central role of Prostaglandin E2-EP1 and EP2 receptor signaling to mediate AJC disassembly through a mechanism that involves PKC and claudin-1 as important target for the TJ-related effects in human colorectal cancer cells (Caco-2).
Tanaka
Marcelo N
MN
Divisão de Biologia Celular, Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil. mtanaka@inca.gov.br
Diaz
Bruno L
BL
de Souza
Wanderley
W
Morgado-Diaz
Jose A
JA
D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D018938:Caco-2 Cells; D002448:Cell Adhesion / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D062445:Claudin-1; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000648:ultrastructure; D015232:Dinoprostone / Q000494:pharmacology*; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D011493:Protein Kinase C / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D015398:Signal Transduction / Q000187:drug effects; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure
C568108:CLDN1 protein, human; D062445:Claudin-1; D008565:Membrane Proteins; C545635:PTGER1 protein, human; C545644:PTGER2 protein, human; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D011493:Protein Kinase C; D015232:Dinoprostone