Bile acids inhibit NAD+-dependent 15-hydroxyprostaglandin dehydrogenase transcription in colonocytes.
Bile acids inhibit NAD+-dependent 15-hydroxyprostaglandin dehydrogenase transcription in colonocytes.
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胆汁酸抑制结肠细胞中 NAD 依赖性 15-羟基前列腺素脱氢酶转录。
DOI：
10.1152/ajpgi.00133.2009
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发表时间：
2009
期刊：
影响因子：
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通讯作者：
Dannenberg,AndrewJ
中科院分区：
文献类型：
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作者：
Miyaki,Akira;Yang,Peiying;Tai,Hsin-Hsiung;Subbaramaiah,Kotha;Dannenberg,AndrewJ
多种证据表明胆汁酸和胰高血糖素（PG）在胃肠道癌发生中的作用。PGE 2的水平由合成和催化两方面决定。以前，胆汁酸介导的环氧合酶-2（考克斯-2）诱导被发现刺激PGE 2合成。NAD+依赖性15-羟基前列腺素脱氢酶（15-PGDH）是负责PGE 2催化的关键酶，与结直肠癌的发生有关。在这项研究中，我们确定胆汁酸是否改变了人结肠癌细胞系中15-PGDH的表达。未结合胆汁酸（鹅脱氧胆酸盐和脱氧胆酸盐）治疗抑制15-PGDH的转录，导致15-PGDH mRNA、蛋白质和酶活性的量减少。结合胆汁酸对15-PGDH表达的抑制作用不如非结合胆汁酸。鹅去氧胆酸盐激活蛋白激酶C（PKC），导致细胞外信号调节激酶（ERK）1/2活性增加。抑制胆汁酸介导的PKC和ERK 1/2活化的小分子也阻断了15-PGDH的下调。胆汁酸诱导早期生长反应因子-1（Egr-1）和Snail，一种结合15-PGDH启动子的抑制性转录因子。沉默Egr-1或Snail阻断鹅脱氧胆酸盐介导的15-PGDH下调。总之，这些数据表明胆汁酸激活信号转导途径PKC → ERK 1/2 → Egr-1 → Snail，从而抑制15-PGDH转录。胆汁酸除了刺激合成外，似乎还通过下调catalysts来增加PG从细胞中的释放。这些结果为胆汁酸与胃肠道癌变之间的联系提供了新的机制见解。
Multiple lines of evidence have suggested a role for both bile acids and prostaglandins (PG) in gastrointestinal carcinogenesis. Levels of PGE2are determined by both synthesis and catabolism. Previously, bile acid-mediated induction of cyclooxygenase-2 (COX-2) was found to stimulate PGE2synthesis. NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for the catabolism of PGE2, 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.