Human carboxylesterase 1A2 expressed from carboxylesterase 1A1 and 1A2 genes is a potent predictor of CPT-11 cytotoxicity in vitro
Human carboxylesterase 1A2 expressed from carboxylesterase 1A1 and 1A2 genes is a potent predictor of CPT-11 cytotoxicity in vitro
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DOI：
10.1097/01.fpc.0000230110.18957.50
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发表时间：
2007-01-01
影响因子：
2.6
通讯作者：
Nishiyama, Masahiko
中科院分区：
文献类型：
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作者：
Tanimoto, Keiji;Kaneyasu, Mika;Nishiyama, Masahiko
背景 CPT-11 通过羧酸酯酶 (CES) 转化为其活性形式 SN-38 是 CPT-11 诱导的细胞毒性中的一个关键事件。在CES中，CES1和CES2可能在代谢中起主要作用，但CES1对CIPT-11反应的功能意义和分子基础仍不清楚。方法和结果我们研究了最近在GenBank注册的CES1A 1 (AB119997)和CES1A2 (AB187225)的CPT-11诱导的细胞毒性，预测了CPT-11的新型生物标志物1 个响应。它们的编码序列显示出高度同源性，仅在N端区域有4个氨基酸差异，但我们对5'区域的测序研究表明，CES1A1和CES1/12在这些区域中具有独特的转录因子共有序列，这意味着基因的转录调控存在差异。我们还鉴定了 CES1A1 基因的三种亚型 - CES1A1a、CES1A1b 和 CES1A1c - 并开发了 CES1A1 和 CES1A2 类型 mRNA 表达的检测方法。有趣的是，CES1A2型mRNA被发现由CES1A1b和CES1A1c亚型以及CES1A2表达，前者的启动子活性高于原始CES1A2基因的启动子活性。最后，CES1A2 类型的 mRNA 表达与癌细胞的 CPT-1 1 敏感性相关。结论我们证明了 CES1A 基因在 CPT-11 1 反应中的新序列结构和功能作用。我们相信，我们的新发现对于开发一种真正有用的 CPT-11 1 化疗敏感性预测方法至关重要。
Background The conversion of CPT-11 to its active form, SN-38, by carboxylesterases (CESs) is a critical event in CPT-11-induced cytotoxicity. Among the CESs, CES1 and CES2 probably play a major role in the metabolism, but the functional significance and molecular basis of CES1 on CIPT-11 response remain unclear.Methods and results We investigated CES1A 1 (AB119997) and CES1A2 (AB187225), whose coding sequences were recently registered in GenBank, for CPT-11-induced cytotoxicity, anticipating novel biomarkers of CPT-11 1 response. Their coding sequences showed high homology, with only four amino acid differences in the N-terminal region, but our sequencing study of the 5' regions revealed that CES1A1 and CES1/12 had distinctive consensus sequences for transcription factors in the regions, implying differences in transcriptional regulation of the genes. We also identified three isoforms of CES1A1 gene - CES1A1a, CES1A1b and CES1A1c - and developed a detection method for CES1A1 and CES1A2 types of mRNA expression. Interestingly, CES1A2 type of mRNA was found to be expressed from both CES1A1b and CES1A1c isoforms and CES1A2, the promoter activity of the former was higher than that of the original CES1A2 gene. Finally, CES1A2 type of mRNA expression correlated with CPT-1 1 sensitivities of cancer cells.Conclusion We demonstrated novel sequence structures and a functional role of CES1A genes in CPT-11 1 responses. We believe that our novel findings will be of key importance in developing a really useful prediction method for CPT-11 1 chemosensitivity.