The 1,2-Diaminocyclohexane Carrier Ligand in Oxaliplatin Induces p53-Dependent Transcriptional Repression of Factors Involved in Thymidylate Biosynthesis
The 1,2-Diaminocyclohexane Carrier Ligand in Oxaliplatin Induces p53-Dependent Transcriptional Repression of Factors Involved in Thymidylate Biosynthesis
复制标题
DOI：
10.1158/1535-7163.mct-14-0748
复制
发表时间：
2015-10-01
影响因子：
5.7
通讯作者：
Kitao, Hiroyuki
中科院分区：
文献类型：
--
作者：
Kiyonari, Shinichi;Iimori, Makoto;Kitao, Hiroyuki
基于铂的化学治疗药物被广泛用作癌症治疗中的联合化学治疗的组分。其中一种药物奥沙利铂与5-氟尿嘧啶（5-FU）和甲酰四氢叶酸联合治疗晚期结肠直肠癌具有协同作用。在p53功能型结直肠癌细胞系HCT 116中，奥沙利铂抑制脱氧尿苷三磷酸酶（dUTR）的表达，dUTR是一种普遍存在的焦磷酸酶，可催化dUTP水解为dUMP并抑制dUTP介导的细胞毒性。然而，该活性的潜在机制尚未完全阐明，并且仍不清楚除dUTR下调以外的因素是否有助于5-FU和奥沙利铂的协同作用。在这项研究中，我们发现奥沙利铂和达铂，铂类药物含有1，2-二氨基环己烷（DACH）载体配体，抑制dUTR（DUT-N）的核亚型的表达，而顺铂和卡铂没有。奥沙利铂诱导早期p53蓄积、原代miR-34 a转录本表达上调以及随后E2 F3和E2 F1下调。非基因毒性激活p53的Nutlin-3a也有类似的作用。miR-34 a模拟物的引入也抑制了E2 F1和DUT-N的表达，表明该miRNA起着致病作用。除DUT-N外，奥沙利铂还以p53依赖性方式抑制编码胸苷酸生物合成相关酶的基因表达。因此，奥沙利铂以p53依赖性方式显著降低dNTP池中的dTTP水平。这些数据表明，奥沙利铂中的DACH载体配体通过p53-miR-34 a-E2 F轴触发信号传导，导致转录调节，最终导致dUTP蓄积和dTTP生物合成减少，可能增强5-FU细胞毒性。(C)2015年AACR。
Platinum-based chemotherapeutic drugs are widely used as components of combination chemotherapy in the treatment of cancer. One such drug, oxaliplatin, exerts a synergistic effect against advanced colorectal cancer in combination with 5-fluorouracil (5-FU) and leucovorin. In the p53-proficient colorectal cancer cell line HCT116, oxaliplatin represses the expression of deoxyuridine triphosphatase (dUTPase), a ubiquitous pyrophosphatase that catalyzes the hydrolysis of dUTP to dUMP and inhibits dUTP-mediated cytotoxicity. However, the underlying mechanism of this activity has not been completely elucidated, and it remains unclear whether factors other than downregulation of dUTPase contribute to the synergistic effect of 5-FU and oxaliplatin. In this study, we found that oxaliplatin and dachplatin, platinum-based drugs containing the 1,2-diaminocyclohexane (DACH) carrier ligand, repressed the expression of nuclear isoform of dUTPase (DUT-N), whereas cisplatin and carboplatin did not. Oxaliplatin induced early p53 accumulation, upregulation of primary miR-34a transcript expression, and subsequent downregulation of E2F3 and E2F1. Nutlin-3a, which activates p53 nongenotoxically, had similar effects. Introduction of miR-34a mimic also repressed E2F1 and DUT-N expression, indicating that this miRNA plays a causative role. In addition to DUT-N, oxaliplatin repressed, in a p53-dependent manner, the expression of genes encoding enzymes involved in thymidylate biosynthesis. Consequently, oxaliplatin significantly decreased the level of dTTP in the dNTP pool in a p53-dependent manner. These data indicate that the DACH carrier ligand in oxaliplatin triggers signaling via the p53-miR-34a-E2F axis, leading to transcriptional regulation that ultimately results in accumulation of dUTP and reduced dTTP biosynthesis, potentially enhancing 5-FU cytotoxicity. (C) 2015 AACR.