Anti-invasive effects of decitabine, a DNA methyltransferase inhibitor,             through tightening of tight junctions and inhibition of matrix metalloproteinase             activities in AGS human gastric carcinoma cells.
The DNA methyltransferase inhibitor decitabine, 5-Aza-2'-deoxycytidine,             possesses anti-metabolic and anticancer activities in various cancer cells. However,             the biochemical mechanisms underlying decitabine-induced inhibition of invasiveness             and metastasis have not been thoroughly studied. In this study, we investigated             the effect of decitabine on the correlation between tightening of tight junctions             (TJs) and anti-invasive activity in AGS human gastric cancer cells. Our data indicated             that the inhibitory effects of decitabine on cell motility and invasiveness were             associated with increased tightness of the TJ, which was demonstrated by an increase             in transepithelial electrical resistance (TER). Immunoblotting results indicated             that decitabine repressed the levels of the claudin proteins, major components             of TJs that play a key role in the control and selectivity of paracellular transport.             Furthermore, matrix metalloproteinase (MMP)-2 and -9 activity in the AGS cells             was dose-dependently inhibited by treatment with decitabine, and this was correlated             with a decrease in mRNA and protein expression. In addition, these effects were             related to inactivation of the phosphoinositide 3-kinase (PI3K)/Akt pathway in             AGS cells. In conclusion, this study suggests that TJs and MMPs are critical targets             of decitabine-induced inhibition of invasiveness in AGS human gastric cancer cells.
Department of Biochemistry, Dongeui University College of Oriental                     Medicine, Busan 614-052, Republic of Korea.
Dong Yeok
DY
Shin
Gi-Young
GY
Kim
Chan Gil
CG
Kim
Wun-Jae
WJ
Kim
Ho Sung
HS
Kang
Yung Hyun
YH
Choi
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D057167:Claudins / Q000378:metabolism; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D053505:Matrix Metalloproteinases, Secreted / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013274:Stomach Neoplasms; D019108:Tight Junctions / Q000187:drug effects* / Q000378:metabolism
D000970:Antineoplastic Agents; D057167:Claudins; D008070:Lipopolysaccharides; D000077209:Decitabine; D015254:DNA Modification Methylases; D051057:Proto-Oncogene Proteins c-akt; D053505:Matrix Metalloproteinases, Secreted; D001374:Azacitidine