Sulindac targets nuclear beta-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines.
Sulindac targets nuclear beta-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines.
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DOI：
10.1038/sj.bjc.6601505
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发表时间：
2004-01-12
影响因子：
8.8
通讯作者：
Pals, S T
中科院分区：
文献类型：
--
作者：
Boon, E M J;Keller, J J;Wormhoudt, T A M;Giardiello, F M;Offerhaus, G J A;van der Neut, R;Pals, S T
非甾体抗炎药(NSAIDs)对结直肠癌(CRC)具有化学预防作用。环氧合酶(COX)-2的抑制是这种作用的部分基础，尽管也可能存在COX-2不依赖的机制。非类固醇抗炎药似乎抑制腺瘤-癌序列的初始阶段，提示与APC/β-连环蛋白/Tcf通路(Wnt-信号通路)有关。因此，我们研究了非甾体抗炎药舒林酸对核(非磷酸化)β-连环蛋白和β-连环蛋白/Tcf介导的转录的影响。对5例家族性腺瘤性息肉病患者治疗前的结直肠腺瘤和舒林酸治疗后的腺瘤进行了核β-连环蛋白的检测。此外，还研究了硫代舒林酸对β-连环蛋白/转录因子介导的转录的影响。与相同患者的腺瘤治疗前相比，经舒林酸治疗6个月后收集的FAP患者腺瘤的核β-连环蛋白表达减少。硫化舒林酸可阻断β-catenin/Tcf介导的转录，并降低非磷酸化β-catenin的水平。结果，舒林酸处理后，正调控的TCF靶标Met和Cyclin D1的蛋白水平下调。本研究提供了体内和体外证据表明，舒林酸可以抑制核β-连环蛋白定位和β-连环蛋白/转录因子调控的靶基因转录。对Wnt信号的抑制为NSAIDs化学预防的COX-2非依赖性机制提供了解释。
Nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive potential against colorectal carcinomas (CRCs). Inhibition of cyclooxygenase (COX)-2 underlies part of this effect, although COX-2-independent mechanisms may also exist. Nonsteroidal anti-inflammatory drugs appear to inhibit the initial stages of the adenoma–carcinoma sequence, suggesting a link to the APC/β-catenin/TCF pathway (Wnt-signalling pathway). Therefore, the effect of the NSAID sulindac on nuclear (nonphosphorylated) β-catenin and β-catenin/TCF-mediated transcription was investigated. Nuclear β-catenin expression was assessed in pretreatment colorectal adenomas and in adenomas after treatment with sulindac from five patients with familial adenomatous polyposis (FAP). Also, the effect of sulindac sulphide on β-catenin/TCF-mediated transcription was studied. Adenomas of FAP patients collected after treatment with sulindac for up to 6 months showed less nuclear β-catenin expression compared to pretreatment adenomas of the same patients. Sulindac sulphide abrogated β-catenin/TCF-mediated transcription in the CRC cell lines DLD1 and SW480, and decreased the levels of nonphosphorylated β-catenin. As a result, the protein levels of the positively regulated TCF targets Met and cyclin D1 were downregulated after sulindac treatment. This study provides in vivo and in vitro evidence that nuclear β-catenin localisation and β-catenin/TCF-regulated transcription of target genes can be inhibited by sulindac. The inhibition of Wnt-signalling provides an explanation for the COX-2-independent mechanism of chemoprevention by NSAIDs.