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Blockage of O-linked GlcNAcylation induces AMPK-dependent autophagy in bladder cancer cells
Cellular & Molecular Biology Letters ( IF 8.3 ) Pub Date : 2020-03-10 , DOI: 10.1186/s11658-020-00208-x
Lu Jin 1 , Feng Yuan 1 , Guangcheng Dai 1 , Qiu Yao 1 , Han Xiang 1 , Lixia Wang 1 , Boxin Xue 1 , Yuxi Shan 1 , Xiaolong Liu 1
Affiliation  

High levels of the post-translational modification O-GlcNAcylation (O-GlcNAc) are found in multiple cancers, including bladder cancer. Autophagy, which can be induced by stress from post-translational modifications, plays a critical role in maintaining cellular homeostasis and regulating tumorigenesis. The impact of O-GlcNAcylation on autophagy in bladder cancer remains unclear. Here, we evaluate the change in autophagic activity in response to O-GlcNAcylation and explore the potential mechanisms. O-GlcNAcylation levels in bladder cancer cells were altered through pharmacological or genetic manipulations: treating with 6-diazo-5-oxo-norleucine (DON) or thiamet-G (TG) or up- and downregulation of O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA). Autophagy was determined using fluorescence microscopy and western blotting. Co-immunoprecipitation (Co-IP) assays were performed to evaluate whether the autophagy regulator AMP-activated protein kinase (AMPK) was O-GlcNAc modified. Cellular autophagic flux was strikingly enhanced as a result of O-GlcNAcylation suppression, whereas it decreased at high O-GlcNAcylation levels. Phosphorylation of AMPK increased after the suppression of O-GlcNAcylation. We found that O-GlcNAcylation of AMPK suppressed the activity of this regulator, thereby inhibiting ULK1 activity and autophagy. We characterized a new function of O-GlcNAcylation in the suppression of autophagy via regulation of AMPK. Blockage of O-linked GlcNAcylation induces AMPK dependent autophagy in bladder cancer cells.

中文翻译:

O-连接的 GlcNAcylation 的阻断诱导膀胱癌细胞中 AMPK 依赖性自噬

在包括膀胱癌在内的多种癌症中发现了高水平的翻译后修饰 O-GlcNAcylation (O-GlcNAc)。自噬可以由翻译后修饰的压力诱导,在维持细胞稳态和调节肿瘤发生中起关键作用。O-GlcNAcylation 对膀胱癌自噬的影响仍不清楚。在这里,我们评估了响应 O-GlcNAcylation 的自噬活性的变化,并探索了潜在的机制。通过药理学或遗传操作改变膀胱癌细胞中的 O-GlcNAc 化水平:用 6-diazo-5-oxo-norleucine (DON) 或 thiamet-G (TG) 治疗或上调和下调 O-GlcNAc 转移酶 (OGT)或 O-GlcNAcase (OGA)。使用荧光显微镜和蛋白质印迹测定自噬。进行免疫共沉淀 (Co-IP) 测定以评估自噬调节剂 AMP 活化蛋白激酶 (AMPK) 是否经过 O-GlcNAc 修饰。由于 O-GlcNAcylation 抑制,细胞自噬通量显着增强,而在高 O-GlcNAcylation 水平时它降低。O-GlcNAcylation 抑制后AMPK 的磷酸化增加。我们发现 AMPK 的 O-GlcNAcylation 抑制了这种调节剂的活性,从而抑制了 ULK1 活性和自噬。我们通过调节 AMPK 表征了 O-GlcNAcylation 在抑制自噬中的新功能。O-连接的 GlcNAcylation 的阻断诱导膀胱癌细胞中 AMPK 依赖性自噬。由于 O-GlcNAcylation 抑制,细胞自噬通量显着增强,而在高 O-GlcNAcylation 水平时它降低。O-GlcNAcylation 抑制后AMPK 的磷酸化增加。我们发现 AMPK 的 O-GlcNAcylation 抑制了这种调节剂的活性,从而抑制了 ULK1 活性和自噬。我们通过调节 AMPK 表征了 O-GlcNAcylation 在抑制自噬中的新功能。O-连接的 GlcNAcylation 的阻断诱导膀胱癌细胞中 AMPK 依赖性自噬。由于 O-GlcNAcylation 抑制,细胞自噬通量显着增强,而在高 O-GlcNAcylation 水平时它降低。O-GlcNAcylation 抑制后AMPK 的磷酸化增加。我们发现 AMPK 的 O-GlcNAcylation 抑制了这种调节剂的活性,从而抑制了 ULK1 活性和自噬。我们通过调节 AMPK 表征了 O-GlcNAcylation 在抑制自噬中的新功能。O-连接的 GlcNAcylation 的阻断诱导膀胱癌细胞中 AMPK 依赖性自噬。从而抑制 ULK1 活性和自噬。我们通过调节 AMPK 表征了 O-GlcNAcylation 在抑制自噬中的新功能。O-连接的 GlcNAcylation 的阻断诱导膀胱癌细胞中 AMPK 依赖性自噬。从而抑制 ULK1 活性和自噬。我们通过调节 AMPK 表征了 O-GlcNAcylation 在抑制自噬中的新功能。O-连接的 GlcNAcylation 的阻断诱导膀胱癌细胞中 AMPK 依赖性自噬。
更新日期:2020-03-10
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