Down-regulation of β-N-acetyl-D-glucosaminidase increases Akt1 activity in thyroid anaplastic cancer cells
Down-regulation of β-N-acetyl-D-glucosaminidase increases Akt1 activity in thyroid anaplastic cancer cells
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DOI：
10.3892/or.2011.1333
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发表时间：
2011-09-01
期刊：
影响因子：
4.2
通讯作者：
Lipinska, Anna
中科院分区：
文献类型：
--
作者：
Krzeslak, Anna;Jozwiak, Pawel;Lipinska, Anna
O-GlcNAc酰化是一种常见的细胞内蛋白质的动态修饰，其中β - n -乙酰氨基葡萄糖片段连接到丝氨酸或苏氨酸残基（O-GlcNAc）的羟基上。越来越多的证据表明，o - glcn酰化在信号转导、转录控制、细胞周期调节和蛋白质降解中起着关键作用。然而，0-GIcNAc修饰在肿瘤发病或进展中的确切作用仍有待确定。在本研究中，我们研究了8305C甲状腺间变性癌细胞中细胞蛋白o - glcn酰化增加对IGF-I信号传导的影响。8305C细胞中O-GlcNAc水平通过下调β - n-乙酰- d -氨基葡萄糖酶（O-GlcNAcase）活性而升高，该酶可去除O-GlcNAc部分。我们在这里证明了IGF-1可以刺激8305C细胞中的Aktl活性，通过化学抑制剂PUGNAc或RNA干扰方法下调O-GlcNAcase活性可以增强这种作用。Akt1激活增加，细胞增殖增加。在O-GlcNAcase活性下调、激酶GSK3 β磷酸化和D中的cycll水平下调的细胞中，其水平高于对照细胞。我们的研究结果表明，PUGNAc或RNAi对O-GlcNAcase处理的8305C细胞增殖的增加至少部分取决于IGF-1-Akt1-GSK3 β -cyclin D-1途径。
O-GlcNAcylation is a common and dynamic modification of intracellular proteins in which beta-N-acetylglucosamine moieties are attached to hydroxyl groups of serine or threonine residues (O-GlcNAc). Accumulating evidence suggests the critical role of protein O-GlcNAcylation in signal transduction, transcriptional control, cell cycle regulation and protein degradation. However, the exact role of 0-GIcNAc modification in tumor pathogenesis or progression remains to be established. In the present study, we investigated the effect of increased O-GlcNAcylation of cellular proteins on IGF-I signaling in 8305C thyroid anaplastic cancer cells. The global O-GlcNAc level in the 8305C cells was increased by down-regulation of beta-N-acetyl-D-glucosaminidase (O-GlcNAcase) activity, an enzyme which removes O-GlcNAc moieties. We demonstrated here that IGF-1 stimulates Aktl activity in 8305C cells, and down-regulation of O-GlcNAcase activity by the chemical inhibitor PUGNAc or RNA interference method enhances this effect. Increased Akt1 activation increased cell proliferation. In cells with downregulation of O-GlcNAcase activity, kinase GSK3 beta phosphorylation and cycl in D, levels were higher than those in control cells. Our findings suggest that increased proliferation of 8305C cells treated with PUGNAc or RNAi against O-GlcNAcase at least partially depends on the IGF-1-Akt1-GSK3 beta-cyclin D-1 pathway.