National Glycoengineering Research Center, Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University, Qingdao, Shandong 266237, P.R. China.
Int J Oncol. 2021 Jun;58(6). doi: 10.3892/ijo.2021.5207. Epub 2021 Apr 13.
‑GlcNAcylation is a dynamic and reversible post‑translational modification of proteins that is modulated by ‑GlcNAc transferase (OGT) and ‑GlcNAcase (OGA). Alterations in the protein expression of ‑linked β‑‑acetylglucosamine (‑GlcNAc) can be induced by multiple factors. However, little is known of the effects of chemotherapeutic agents on ‑GlcNAcylation and the relevant molecular mechanisms in cancer cells. In the present study, to investigate whether cisplatin alters protein ‑GlcNAcylation and to explore whether protein ‑GlcNAc modification affects the antitumor activity of cisplatin, experiments were performed and . The results indicated that cisplatin treatment resulted in an enhancement of global protein ‑GlcNAc levels in the H1299, Hep G2 and MCF‑7 cells and . Cisplatin upregulated the protein and mRNA expression levels of OGT and OGA in H1299 cells. Moreover, cisplatin induced the significant enhancement of the enzymatic activity of OGT in H1299 cells. On the contrary, the activation of OGA decreased in response to cisplatin exposure in H1299 cells. Cisplatin inhibited the activity of AMP‑activated protein kinase (AMPK) by decreasing the AMP/ATP ratio. The present study also revealed that the decreased AMPK activation inhibited glutamine‑fructose‑6‑phosphate aminotransferase (isomerizing) 1 (GFAT1) phosphorylation and subsequently promoted the activity of GFAT1. Cisplatin‑induced GFAT1 activation elevated the production of the donor substrate, uridine 5‑diphospho‑N‑acetylglucosamine (UDP‑GlcNAc). However, alterations in the ‑GlcNAc levels by the inhibition of OGT and OGA did not affect the sensitivity of lung cancer cells to cisplatin. On the whole, the present study demonstrates that cisplatin enhances protein ‑GlcNAcylation by altering the activity of OGT, OGA and AMPK and .
‑GlcNAc 酰化是蛋白质的一种动态和可逆的翻译后修饰，由‑GlcNAc 转移酶（OGT）和‑GlcNAcase（OGA）调节。多种因素可诱导蛋白质表达中连接的 β‑‑乙酰葡萄糖胺（‑GlcNAc）的改变。然而，关于化疗药物对‑GlcNAc 酰化的影响以及癌细胞中相关的分子机制知之甚少。在本研究中，为了研究顺铂是否改变蛋白质的‑GlcNAc 酰化，并探讨蛋白质的‑GlcNAc 修饰是否影响顺铂的抗肿瘤活性，进行了实验。结果表明，顺铂处理导致 H1299、Hep G2 和 MCF‑7 细胞中整体蛋白质‑GlcNAc 水平升高。顺铂上调了 H1299 细胞中 OGT 和 OGA 的蛋白和 mRNA 表达水平。此外，顺铂诱导 H1299 细胞中 OGT 的酶活性显著增强。相反，H1299 细胞中，顺铂暴露导致 OGA 的活性降低。顺铂通过降低 AMP/ATP 比值抑制 AMP 激活的蛋白激酶（AMPK）的活性。本研究还揭示，AMPK 激活的减少抑制了谷氨酰胺‑果糖‑6‑磷酸氨基转移酶（异构酶）1（GFAT1）的磷酸化，随后促进了 GFAT1 的活性。顺铂诱导的 GFAT1 激活增加了供体底物尿苷二磷酸‑N‑乙酰葡萄糖胺（UDP‑GlcNAc）的产生。然而，OGT 和 OGA 抑制对肺癌细胞对顺铂敏感性的改变并未影响。总的来说，本研究表明，顺铂通过改变 OGT、OGA 和 AMPK 的活性来增强蛋白质的‑GlcNAc 酰化。
