Bile acids inhibit NAD+-dependent 15-hydroxyprostaglandin dehydrogenase transcription in colonocytes.
Multiple lines of evidence have suggested a role for both bile acids and prostaglandins (PG) in gastrointestinal carcinogenesis. Levels of PGE(2) are determined by both synthesis and catabolism. Previously, bile acid-mediated induction of cyclooxygenase-2 (COX-2) was found to stimulate PGE(2) synthesis. NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for the catabolism of PGE(2), has been linked to colorectal carcinogenesis. In this study, we determined whether bile acids altered the expression of 15-PGDH in human colon cancer cell lines. Treatment with unconjugated bile acids (chenodeoxycholate and deoxycholate) suppressed the transcription of 15-PGDH, resulting in reduced amounts of 15-PGDH mRNA, protein, and enzyme activity. Conjugated bile acids were less potent suppressors of 15-PGDH expression than unconjugated bile acids. Treatment with chenodeoxycholate activated protein kinase C (PKC), leading in turn to increased extracellular signal-regulated kinase (ERK) 1/2 activity. Small molecules that inhibited bile acid-mediated activation of PKC and ERK1/2 also blocked the downregulation of 15-PGDH. Bile acids induced early growth response factor-1 (Egr-1) and Snail, a repressive transcription factor that bound to the 15-PGDH promoter. Silencing Egr-1 or Snail blocked chenodeoxycholate-mediated downregulation of 15-PGDH. Together, these data indicate that bile acids activate the signal transduction pathway PKC --> ERK1/2 --> Egr-1 --> Snail and thereby suppress 15-PGDH transcription. Bile acids appear to increase the release of PGs from cells by downregulating catabolism in addition to stimulating synthesis. These results provide new mechanistic insights into the link between bile acids and gastrointestinal carcinogenesis.
Miyaki
Akira
A
Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
Yang
Peiying
P
Tai
Hsin-Hsiung
HH
Subbaramaiah
Kotha
K
Dannenberg
Andrew J
AJ
D001665:Binding Sites; D002635:Chenodeoxycholic Acid / Q000378:metabolism*; D003106:Colon / Q000201:enzymology*; D003840:Deoxycholic Acid / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D019073:HT29 Cells; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
D051766:Early Growth Response Protein 1; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D003840:Deoxycholic Acid; D002635:Chenodeoxycholic Acid; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015232:Dinoprostone