N-myc downstream-regulated gene 1 promotes oxaliplatin-triggered apoptosis in colorectal cancer cells via enhancing the ubiquitination of Bcl-2.
N-myc downstream-regulated gene 1 promotes oxaliplatin-triggered apoptosis in colorectal cancer cells via enhancing the ubiquitination of Bcl-2.
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N-myc下游调控基因1通过增强Bcl-2泛素化促进奥沙利铂引发的结直肠癌细胞凋亡
DOI：
10.18632/oncotarget.17711
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发表时间：
2017-07-18
期刊：
影响因子：
--
通讯作者：
Zheng M
中科院分区：
文献类型：
--
作者：
Yang X;Zhu F;Yu C;Lu J;Zhang L;Lv Y;Sun J;Zheng M
N-myc下游调节基因1（NDRG 1）是一种有效的肿瘤抑制基因。NDRG 1抗肿瘤活性的分子机制涉及其对多种致瘤信号通路的抑制作用。本研究旨在探讨NDRG 1在大肠癌细胞凋亡中的作用。我们首先收集了在我们医疗中心接受奥沙利铂为基础的新辅助化疗的局部晚期直肠癌（LARC）患者的临床数据。相关分析显示NDRG 1与患者的降级率和预后呈正相关。在此基础上，研究NDRG 1基因过表达和缺失对大肠癌细胞凋亡的影响。NDRG 1过表达促进结直肠癌细胞凋亡，而NDRG 1缺失导致对奥沙利铂治疗的耐药性。此外，我们观察到，Bcl-2，一个主要的抗凋亡蛋白，是由NDRG 1在转录后水平的调控。NDRG 1通过与Bcl-2的经典调节因子蛋白激酶Cα（PKCα）结合，促进Bcl-2的泛素化和降解，从而促进结直肠癌细胞凋亡。此外，NDRG 1在小鼠异种移植模型中抑制肿瘤生长并促进细胞凋亡。总之，NDRG 1促进奥沙利铂触发的结直肠癌细胞凋亡。因此，结直肠癌患者可以通过NDRG 1的表达水平进行分层。NDRG 1阳性患者可能受益于含奥沙利铂的化疗方案，而NDRG 1表达阴性的患者应避免使用这种细胞毒性药物。
N-myc downstream-regulated gene1 (NDRG1) has been identified as a potent tumor suppressor gene. The molecular mechanisms of anti-tumor activity of NDRG1 involve its suppressive effects on a variety of tumorigenic signaling pathways. The purpose of this study was to investigate the role of NDRG1 in the apoptosis of colorectal cancer (CRC) cells. We first collected the clinical data of locally advanced rectal cancer (LARC) patients receiving oxaliplatin-based neoadjuvant chemotherapy in our medical center. Correlation analysis revealed that NDRG1 positively associated with the downstaging rates and prognosis of patients. Then, the effects of over-expression and depletion of NDRG1 gene on apoptosis of colorectal cancer were tested in vitro and in vivo. NDRG1 over-expression promoted apoptosis in colorectal cancer cells whereas depletion of NDRG1 resulted in resistance to oxaliplatin treatment. Furthermore, we observed that Bcl-2, a major anti-apoptotic protein, was regulated by NDRG1 at post-transcriptional level. By binding Protein kinase Cα (PKCα), a classical regulating factor of Bcl-2, NDRG1 enhanced the ubiquitination and degradation of Bcl-2, thus promoting apoptosis in CRC cells. In addition, NDRG1 inhibited tumor growth and promoted apoptosis in mouse xenograft model. In conclusion, NDRG1 promotes oxaliplatin-triggered apoptosis in colorectal cancer. Therefore, colorectal cancer patients can be stratified by the expression level of NDRG1. NDRG1-positive patients may benefit from oxaliplatin-containing chemotherapy regimens whereas those with negative NDRG1 expression should avoid the usage of this cytotoxic drug.
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影响因子：
3.7
作者：
Mao Z;Sun J;Feng B;Ma J;Zang L;Dong F;Zhang D;Zheng M
通讯作者：
Zheng M
影响因子：
4.7
作者：
Lu, Wen-Jing;Chua, Mei-Sze;So, Samuel K.
通讯作者：
So, Samuel K.
影响因子：
4.6
作者：
Luo EC;Chang YC;Sher YP;Huang WY;Chuang LL;Chiu YC;Tsai MH;Chuang EY;Lai LC
通讯作者：
Lai LC
释放的 Bim 与 Mcl-1 的结合是 ABT-199 内在耐药性的机制，可通过与 AML 细胞中的柔红霉素或阿糖胞苷组合来克服
DOI：
10.1158/1078-0432.ccr-15-3057
发表时间：
2016-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Niu X;Zhao J;Ma J;Xie C;Edwards H;Wang G;Caldwell JT;Xiang S;Zhang X;Chu R;Wang ZJ;Lin H;Taub JW;Ge Y
通讯作者：
Ge Y
影响因子：
4
作者：
Jin, Runsen;Liu, Wensheng;Richardson, Des R.
通讯作者：
Richardson, Des R.