Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells.
Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells.
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DOI：
10.1038/nchembio.2194
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发表时间：
2016-12
影响因子：
14.8
通讯作者：
Contessa JN
中科院分区：
文献类型：
--
作者：
Lopez-Sambrooks C;Shrimal S;Khodier C;Flaherty DP;Rinis N;Charest JC;Gao N;Zhao P;Wells L;Lewis TA;Lehrman MA;Gilmore R;Golden JE;Contessa JN
天冬酰胺(N)连接的糖基化是一种对糖蛋白折叠、稳定性和细胞定位至关重要的蛋白质修饰。为了确定在这一生物合成途径中抑制新靶点的小分子，我们发起了基于细胞的高通量筛选和领导化合物优化活动，提供了一种细胞通透性抑制剂(NGI-1)。NGI-1以寡糖转移酶(OST)为靶标，OST是一种异源寡聚酶，以多种异构体存在，将寡糖转移到受体蛋白。在非小细胞肺癌细胞中，NGI-1阻断细胞表面EGFR糖蛋白的定位和信号传递，但选择性地阻止那些依赖EGFR(或FGFR)生存的细胞系的增殖。在这些细胞系中，OST抑制导致细胞周期停滞，伴随着p21的诱导，自体荧光和细胞形态的改变，所有这些都是衰老的标志。这些结果证实了OST抑制是治疗受体酪氨酸激酶依赖性肿瘤的一种潜在的治疗方法，并为可逆地调节哺乳动物细胞中N-连接的糖基化提供了化学探针。
Asparagine (N)-linked glycosylation is a protein modification critical for glycoprotein folding, stability, and cellular localization. To identify small molecules that inhibit new targets in this biosynthetic pathway, we initiated a cell-based high throughput screen and lead compound optimization campaign that delivered a cell permeable inhibitor (NGI-1). NGI-1 targets the oligosaccharyltransferase (OST), a hetero-oligomeric enzyme that exists in multiple isoforms and transfers oligosaccharides to recipient proteins. In non-small cell lung cancer cells NGI-1 blocks cell surface localization and signaling of the EGFR glycoprotein, but selectively arrests proliferation in only those cell lines that are dependent on EGFR (or FGFR) for survival. In these cell lines OST inhibition causes cell cycle arrest accompanied by induction of p21, autofluorescence, and changes in cell morphology; all hallmarks of senescence. These results identify OST inhibition as a potential therapeutic approach for treating receptor tyrosine kinase-dependent tumors and provides a chemical probe for reversibly regulating N-linked glycosylation in mammalian cells.