泽布勒林通过p53依赖的内质网应激抑制结直肠癌的肿瘤发生和干性。

Zebularine inhibits tumorigenesis and stemness of colorectal cancer via p53-dependent endoplasmic reticulum stress.

作者信息

Yang Pei-Ming, Lin Yi-Ting, Shun Chia-Tung, Lin Shan-Hu, Wei Tzu-Tang, Chuang Shu-Hui, Wu Ming-Shiang, Chen Ching-Chow

机构信息

1] Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan [2] The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan [3].

出版信息

Sci Rep. 2013 Nov 14;3:3219. doi: 10.1038/srep03219.

Aberrant DNA hypermethylation is frequently found in tumor cells and inhibition of DNA methylation is an effective anticancer strategy. In this study, the therapeutic effect of DNA methyltransferase (DNMT) inhibitor zebularine (Zeb) on colorectal cancer (CRC) was investigated. Zeb exhibited anticancer activity in cell cultures, tumor xenografts and mouse colitis-associated CRC model. It stabilizes p53 through ribosomal protein S7 (RPS7)/MDM2 pathways and DNA damage. Zeb-induced cell death was dependent on p53. Microarray analysis revealed that genes related to endoplasmic reticulum (ER) stress and unfolded protein response (UPR) were affected by Zeb. Zeb induced p53-dependent ER stress and autophagy. Pro-survival markers of ER stress/UPR (GRP78) and autophagy (p62) were increased in tumor tissues of CRC patients, AOM/DSS-induced CRC mice and HCT116-derived colonospheres. Zeb downregulates GRP78 and p62, and upregulates a pro-apoptotic CHOP. Our results reveal a novel mechanism for the anticancer activity of Zeb.

异常的DNA高甲基化在肿瘤细胞中经常被发现，抑制DNA甲基化是一种有效的抗癌策略。在本研究中，研究了DNA甲基转移酶（DNMT）抑制剂泽布替尼（Zeb）对结直肠癌（CRC）的治疗效果。Zeb在细胞培养、肿瘤异种移植和小鼠结肠炎相关的CRC模型中表现出抗癌活性。它通过核糖体蛋白S7（RPS7）/MDM2途径和DNA损伤使p53稳定。Zeb诱导的细胞死亡依赖于p53。微阵列分析显示，与内质网（ER）应激和未折叠蛋白反应（UPR）相关的基因受到Zeb的影响。Zeb诱导p53依赖的ER应激和自噬。ER应激/UPR的促生存标志物（GRP78）和自噬的促生存标志物（p62）在CRC患者、AOM/DSS诱导的CRC小鼠和HCT116衍生的结肠球的肿瘤组织中增加。Zeb下调GRP78和p62，并上调促凋亡的CHOP。我们的结果揭示了Zeb抗癌活性的一种新机制。