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首页> 外文期刊>British Journal of Cancer >Increased NF-|[kappa]|B DNA binding but not transcriptional activity during apoptosis induced by the COX-2-selective inhibitor NS-398 in colorectal carcinoma cells
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Increased NF-|[kappa]|B DNA binding but not transcriptional activity during apoptosis induced by the COX-2-selective inhibitor NS-398 in colorectal carcinoma cells

机译：在结肠直肠癌细胞中由COX-2选择性抑制剂NS-398诱导的凋亡过程中NF- |κ| B DNA结合增加，但转录活性没有

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Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit colorectal neoplasia, an effect that is associated with their ability to induce apoptosis. Although NSAIDs have been reported to inhibit NF-κB, more recent studies show activation of NF-κB by NSAIDs. NF-κB commonly shows antiapoptotic activity and is implicated in the therapeutic resistance of cancer cells. The effects of highly COX-2-selective NSAIDs such as NS-398 on NF-κB in colorectal tumour cells have not been reported. Therefore, we addressed whether NF-κB has a role in NS-398-induced apoptosis of colorectal cancer cells. Treatment of HT-29 colorectal carcinoma cells with doses of NS-398 (50–75?μM) known to induce apoptosis had no effect on NF-κB for up to 48?h. However after 72 and 96?h NF-κB DNA-binding activity was increased by NS-398, in parallel with apoptosis induction. NS-398-treated HT-29 cells showed increased p50 homodimer binding and an induction of p50/p65 heterodimers, as demonstrated by supershift assay. However, although NS-398 increased NF-κB DNA binding it did not increase NF-κB-dependent reporter activity and inhibition of NF-κB DNA binding did not enhance NS-398-induced apoptosis. This indicates that NF-κB activated by NS-398 is transcriptionally inactive and is an encouraging result for the use of COX-2-selective NSAIDs not only in chemoprevention but also as novel therapies for colon cancer.
机译：非甾体类抗炎药（NSAIDs）抑制结直肠瘤形成，这一作用与其诱导凋亡的能力有关。尽管已经报道了NSAID抑制NF-κB，但最近的研究表明NSAID激活了NF-κB。 NF-κB通常显示抗凋亡活性，并与癌细胞的治疗抗性有关。尚未报道高COX-2选择性NSAID（例如NS-398）对结直肠肿瘤细胞中NF-κB的影响。因此，我们探讨了NF-κB是否在NS-398诱导的大肠癌细胞凋亡中起作用。已知能诱导细胞凋亡的NS-398（50–75？μM）剂量对HT-29大肠癌细胞的作用长达48？h对NF-κB无影响。然而，在72和96小时后，NS-398增加了NF-κB的DNA结合活性，同时诱导了细胞凋亡。 NS-398处理的HT-29细胞显示出增加的p50同二聚体结合和对p50 / p65异二聚体的诱导，如超位移测定所证实。但是，尽管NS-398增加了NF-κBDNA的结合，但并未增加NF-κB依赖的报道分子的活性，抑制NF-κBDNA结合并没有增强NS-398诱导的细胞凋亡。这表明被NS-398激活的NF-κB在转录上是无活性的，这对于将COX-2选择性NSAIDs不仅用于化学预防中，而且还作为结肠癌的新疗法，是令人鼓舞的结果。

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