Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells.
Deoxycholate induces COX-2 expression via Erk1/2-, p38-MAPK and AP-1-dependent mechanisms in esophageal cancer cells.
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DOI：
10.1186/1471-2407-9-190
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发表时间：
2009-06-17
期刊：
影响因子：
3.8
通讯作者：
Kelleher D
中科院分区：
文献类型：
--
作者：
Looby E;Abdel-Latif MM;Athié-Morales V;Duggan S;Long A;Kelleher D
从Barrett化生到腺癌的进展与获得抗肿瘤表型有关。胆汁酸脱氧胆酸盐（DCA）被认为在食管腺癌的发生发展中起重要作用，但其确切的分子机制尚不清楚。本研究的目的是探讨DCA刺激的考克斯-2信号通路及其对食管腺癌细胞存活和凋亡的影响。在SKGT-4细胞暴露于DCA后，通过免疫印迹检测考克斯-2、MAPK和PARP的蛋白水平。AP-1活性通过迁移率改变分析来评估。DNA片段化法和MTT法检测DCA的毒性。DCA诱导AP-1转录因子的持续激活，其中Fra-1和JunB被鉴定为DCA诱导的AP-1复合物的主要组分。DCA通过Erk 1/2和p38 MAPK激活Fra-1，而Erk 1/2位于JunB的上游。此外，DCA刺激介导增殖抑制，伴随低水平的caspase-3依赖性PARP裂解和DNA片段化。DCA通过MAPK/AP-1途径诱导抗凋亡蛋白考克斯-2似乎平衡了DCA介导的促凋亡标志物如PARP切割和DNA片段化的活化。在DCA暴露前，通过阿司匹林预处理抑制考克斯-2后，这两种标志物均升高。DCA调节食管细胞中的凋亡和考克斯-2调节的细胞存活，这表明这两种相反信号之间的平衡可能决定DCA作为反流物的组分的转化潜力。
The progression from Barrett's metaplasia to adenocarcinoma is associated with the acquirement of an apoptosis-resistant phenotype. The bile acid deoxycholate (DCA) has been proposed to play an important role in the development of esophageal adenocarcinoma, but the precise molecular mechanisms remain undefined. The aim of this study was to investigate DCA-stimulated COX-2 signaling pathways and their possible contribution to deregulated cell survival and apoptosis in esophageal adenocarcinoma cells. Following exposure of SKGT-4 cells to DCA, protein levels of COX-2, MAPK and PARP were examined by immunoblotting. AP-1 activity was assessed by mobility shift assay. DCA-induced toxicity was assessed by DNA fragmentation and MTT assay. DCA induced persistent activation of the AP-1 transcription factor with Fra-1 and JunB identified as the predominant components of the DCA-induced AP-1 complex. DCA activated Fra-1 via the Erk1/2- and p38 MAPK while Erk1/2 is upstream of JunB. Moreover, DCA stimulation mediated inhibition of proliferation with concomitant low levels of caspase-3-dependent PARP cleavage and DNA fragmentation. Induction of the anti-apoptotic protein COX-2 by DCA, via MAPK/AP-1 pathway appeared to balance the DCA mediated activation of pro-apoptotic markers such as PARP cleavage and DNA fragmentation. Both of these markers were increased upon COX-2 suppression by aspirin pretreatment prior to DCA exposure. DCA regulates both apoptosis and COX-2-regulated cell survival in esophageal cells suggesting that the balance between these two opposing signals may determine the transformation potential of DCA as a component of the refluxate.
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影响因子：
4.4
作者：
Athie-Morales, V;Smits, HH;Hilkens, CMU
通讯作者：
Hilkens, CMU
影响因子：
--
作者：
HOLT, PR
通讯作者：
HOLT, PR
DOI：
10.1111/j.1432-1033.1997.00726.x
发表时间：
1997-02-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Bauer, MKA;Lieb, K;Fiebich, BL
通讯作者：
Fiebich, BL
影响因子：
8
作者：
Lallemand, D;Spyrou, G;Pfarr, CM
通讯作者：
Pfarr, CM
影响因子：
4.8
作者：
Chalmers, Claire J.;Gilley, Rebecca;Cook, Simon J.
通讯作者：
Cook, Simon J.