Nonsteroidal anti-inflammatory drugs induce colorectal cancer cell apoptosis by suppressing 14-3-3ε
Nonsteroidal anti-inflammatory drugs induce colorectal cancer cell apoptosis by suppressing 14-3-3ε
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DOI：
10.1158/0008-5472.can-06-3431
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发表时间：
2007-04-01
期刊：
影响因子：
11.2
通讯作者：
Wu, Kenneth K.
中科院分区：
文献类型：
--
作者：
Liou, Jun-Yang;Ghelani, Dipak;Wu, Kenneth K.
为了确定14 - 3 - 3在非甾体抗炎药（NSAID）诱导的结直肠癌细胞凋亡中的作用，我们评估了舒林酸对结直肠癌细胞中14 - 3 - 3 β蛋白表达的影响。舒林酸硫化物以时间和浓度依赖性方式抑制HT-29和DLD-1细胞中的14 - 3 - 3 β蛋白。600 μ mol/L的舒林酸砜抑制HT-29中14 - 3 - 3 β蛋白的表达。吲哚美辛和选择性环氧合酶-2（考克斯-2）抑制剂SC-236的作用与舒林酸相似。舒林酸抑制14 - 3 - 3 β启动子活性。由于14 - 3 - 3 epsilon启动子激活是由过氧化物酶体增殖物激活受体δ（PPARdelta）介导的，因此我们确定了14 - 3 - 3 epsilon抑制与非甾体抗炎药对PPARdelta抑制之间的相关性。舒林酸硫化物抑制PPAR δ蛋白表达和PPAR δ转录活性。通过腺病毒转移过表达的PPARdelta使14 - 3 - 3 β蛋白免于被舒林酸或吲哚美辛消除。NSAID诱导的14 - 3 - 3e抑制与细胞溶质Bad降低、线粒体Bad升高和细胞凋亡增加相关，Ad-PPAR8转导可挽救细胞凋亡。HT-29中14 - 3 - 3 β的稳定表达可显著保护细胞免于凋亡。我们的发现揭示了NSAID通过PPAR δ/14 - 3 - 3 β转录途径诱导结直肠癌细胞凋亡的新机制。这些结果提示14 - 3 - 3 β是大肠癌预防和治疗的一个靶点。
To determine the role of 14-3-3 in colorectal cancer apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs), we evaluated the effects of sulindac on 14-3-3 epsilon protein expression in colorectal cancer cells. Sulindac sulfide inhibited 14-3-3 epsilon proteins in HT-29 and DLD-1 cells in a time- and concentration-dependent manner. Sulindac sulfone at 600 mu mol/L inhibited 14-3-3 epsilon protein expression in HT-29. Indomethacin and SC-236, a selective cyclooxygenase-2 (COX-2) inhibitor, exerted a similar effect as sulindac. Sulindac suppressed 14-3-3 epsilon promoter activity. As 14-3-3 epsilon promoter activation is mediated by peroxisome proliferator-activated receptor delta (PPAR delta), we determined the correlation between 14-3-3 epsilon inhibition and PPAR delta suppression by NSAIDs. Sulindac sulfide inhibited PPAR delta protein expression and PPAR delta transcriptional activity. Overexpression of PPAR delta by adenoviral transfer rescued 14-3-3 epsilon proteins from elimination by sulindac or indomethacin. NSAID-induced 14-3-3e suppression was associated with reduced cytosolic Bad with elevation of mitochondrial Bad and increase in apoptosis which was rescued by Ad-PPAR8 transduction. Stable expression of 14-3-3 epsilon in HT-29 significantly protected cells from apoptosis. Our findings shed light on a novel mechanism by which NSAIDs induce colorectal cancer apoptosis via the PPAR delta/14-3-3 epsilon transcriptional pathway. These results suggest that 14-3-3 epsilon is a target for the prevention and therapy of colorectal cancer.