Glucose deprivation induces G2/M transition-arrest and cell death in N-GlcNAc2-modified protein-producing renal carcinoma cells.
Glucose deprivation induces G2/M transition-arrest and cell death in N-GlcNAc2-modified protein-producing renal carcinoma cells.
复制标题
DOI：
10.1371/journal.pone.0096168
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Yuasa T
中科院分区：
文献类型：
--
作者：
Isono T;Chano T;Kitamura A;Yuasa T
在肿瘤的微环境中，一些癌细胞可以在缺糖的情况下存活。最近，我们报道了N-连接的(β-N-乙酰氨基葡萄糖)2[N-GlcNAc2]修饰的蛋白质在缺糖条件下诱导G2/M期停滞和细胞死亡。在这里，我们调查了这种对缺糖的反应是否有助于肾癌的生存，肾癌对营养压力很敏感。具体地说，我们分析了七个肾癌细胞株。其中四个细胞系产生N-GlcNAc2修饰的蛋白质，并在葡萄糖剥夺下导致G2/M期停滞，导致细胞死亡。其余三株细胞不产生N-GlcNAc2修饰的蛋白质，在缺糖条件下发生G1/S期停滞，从而存活下来。4个死亡细胞系的UDP-GlcNAc生物合成途径显著上调，P53的磷酸化增强，而存活的3个细胞系没有观察到这一点。此外，4个死亡细胞株显示ATF3的表达持续上调，这与未折叠蛋白反应(UPR)有关，而存活的3个细胞株仅显示短暂的ATF3上调。在这项研究中，我们证明了在缺糖条件下积聚N-GlcNAc2修饰蛋白的肾癌细胞不能存活，UPR途径异常延长。相比之下，在这些条件下不积累N-GlcNAc2修饰蛋白的肾癌细胞可以存活下来。此外，我们还证明了UPR抑制剂布福明有效地降低了葡萄糖剥夺条件下敏感和耐药表型的细胞存活率。进一步澄清这些发现的研究将导致肾癌化疗新疗法的发展。
Some cancer cells can survive under glucose deprivation within the microenvironment of a tumor. Recently, we reported that N-linked (β-N-acetylglucosamine)2 [N-GlcNAc2]-modified proteins induce G2/M arrest and cell death under glucose deprivation. Here, we investigated whether such a response to glucose deprivation contributes to the survival of renal cell carcinomas, which are sensitive to nutritional stress. Specifically, we analyzed seven renal carcinoma cell lines. Four of these cell lines produced N-GlcNAc2-modified proteins and led G2/M-phase arrest under glucose deprivation, leading to cell death. The remaining three cell lines did not produce N-GlcNAc2-modified proteins and undergo G1/S-phase arrest under glucose deprivation, leading to survival. The four dead cell lines displayed significant up-regulation in the UDP-GlcNAc biosynthesis pathway as well as increased phosphorylation of p53, which was not observed in the surviving three cell lines. In addition, the four dead cell lines showed prolonged up-regulated expression of ATF3, which is related to unfolded protein response (UPR), while the surviving three cell lines showed only transient up-regulation of ATF3. In this study, we demonstrated that the renal carcinoma cells which accumulate N-GlcNAc2-modified proteins under glucose deprivation do not survive with abnormaly prolonged UPR pathway. By contrast, renal carcinoma cells that do not accumulate N-GlcNAc2-modified proteins under these conditions survive. Morover, we demonstrated that buformin, a UPR inhibitor, efficiently reduced cell survival under conditions of glucose deprivation for both sensitive and resistant phenotypes. Further studies to clarify these findings will lead to the development of novel chemotherapeutic treatments for renal cancer.
登录
查看更多内容
影响因子：
45.3
作者：
Busaidy, Naifa L.;Farooki, Azeez;Siu, Lillian L.
通讯作者：
Siu, Lillian L.
影响因子：
11.2
作者：
Saito, Sakae;Furuno, Aki;Tomida, Akihiro
通讯作者：
Tomida, Akihiro
乳酸性酸中毒在癌细胞抵抗葡萄糖剥夺诱导的细胞死亡中的核心作用
影响因子：
7.3
作者：
Wu, Hao;Ding, Zonghui;Hu, Xun
通讯作者：
Hu, Xun
DOI：
10.1152/ajpheart.00756.2008
发表时间：
2009-03-01
影响因子：
4.8
作者：
Rajapakse, Angana Gupta;Ming, Xiu-Fen;Yang, Zhihong
通讯作者：
Yang, Zhihong
影响因子：
3.7
作者：
Isono T
通讯作者：
Isono T