AGRO100 inhibits activation of nuclear factor-κB (NF-κB) by forming a complex with NF-κB essential modulator (NEMO) and nucleolin
AGRO100 inhibits activation of nuclear factor-κB (NF-κB) by forming a complex with NF-κB essential modulator (NEMO) and nucleolin
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DOI：
10.1158/1535-7163.mct-05-0361
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发表时间：
2006-07-01
影响因子：
5.7
通讯作者：
Bates, Paula J.
中科院分区：
文献类型：
--
作者：
Girvan, Allicia C.;Teng, Yun;Bates, Paula J.
AGRO 100，也被称为AS 1411，是一种实验性抗癌药物，最近进入人体临床试验。它是一类称为富含G的寡核苷酸（GRO）的新型抗增殖剂的成员，GRO是非反义、富含鸟苷的磷酸二酯寡脱氧核苷酸，可形成稳定的G-四链体结构。GRO的生物活性是由于它们与作为适体的特定细胞蛋白质结合。GRO的一个重要靶蛋白先前已被鉴定为核仁素，其是癌细胞以高水平表达的多功能蛋白。在这里，我们报告，AGRO 100还与核因子-κ B（NF-κ B）必需调节剂（NEMO），这是一个调节亚基的抑制剂κ B（I κ B）激酶（IKK）复合物，也被称为IKK γ。在经典的NF-κ B途径中，IKK复合物是I κ B α磷酸化和随后转录因子NF-κ B活化所必需的。我们发现用AGRO 100治疗癌细胞抑制IKK活性，并减少I κ B α对肿瘤坏死因子-α刺激的磷酸化反应。使用报告基因分析，我们发现，AGRO 100块肿瘤坏死因子-α诱导的和组成性NF-κ B的活性在人类癌细胞系来自宫颈癌，前列腺癌，乳腺癌和肺癌。此外，我们发现，在AGRO 100处理的癌细胞中，NEMO被核仁素共沉淀，表明这两种蛋白质存在于同一复合物中。我们的研究表明，NF-κ B活性的消除可能有助于AGRO 100的抗癌作用，核仁素可能在调节NF-κ B通路中发挥以前未知的作用。
AGRO100, also known as AS1411, is an experimental anticancer drug that recently entered human clinical trials. It is a member of a novel class of antiproliferative agents known as G-rich oligonucleotides (GRO), which are nonantisense, guanosine-rich phosphodiester oligodeoxynucleotides that form stable G-quadruplex structures. The biological activity of GROs results from their binding to specific cellular proteins as aptamers. One important target protein of GROs has been previously identified as nucleolin, a multifunctional protein expressed at high levels by cancer cells. Here, we report that AGRO100 also associates with nuclear factor-kappa B (NF-kappa B) essential modulator (NEMO), which is a regulatory subunit of the inhibitor of kappa B (I kappa B) kinase (IKK) complex, and also called IKK gamma. In the classic NF-kappa B pathway, the IKK complex is required for phosphorylation of I kappa B alpha and subsequent activation of the transcription factor NF-kappa B. We found that treatment of cancer cells with AGRO100 inhibits IKK activity and reduces phosphorylation of I kappa B alpha in response to tumor necrosis factor-alpha stimulation. Using a reporter gene assay, we showed that AGRO100 blocks both tumor necrosis factor-alpha-induced and constitutive NF-kappa B activity in human cancer cell lines derived from cervical, prostate, breast, and lung carcinomas. In addition, we showed that, in AGRO100-treated cancer cells, NEMO is coprecipitated by nucleolin, indicating that both proteins are present in the same complex. Our studies suggest that abrogation of NF-kappa B activity may contribute to the anticancer effects of AGRO100 and that nucleolin may play a previously unknown role in regulating the NF-kappa B pathway.