The methyltransferase inhibitor 5-aza-2-deoxycytidine induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells
The methyltransferase inhibitor 5-aza-2-deoxycytidine induces apoptosis via induction of 15-lipoxygenase-1 in colorectal cancer cells
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DOI：
10.1158/1535-7163.mct-05-0218
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发表时间：
2005-11-01
影响因子：
5.7
通讯作者：
Lippman, SM
中科院分区：
文献类型：
--
作者：
Hsi, LC;Xi, XP;Lippman, SM
富含 CpG 的基因启动子区域中的 DNA 甲基转移导致的 DNA 甲基化是人类细胞中表观遗传沉默的一个众所周知的组成部分。癌细胞中这一过程的失调可能会导致启动子 CpG 岛过度甲基化，从而禁用某些基因（例如肿瘤抑制基因）的转录起始。逆转表观遗传沉默和上调参与预防或逆转恶性表型的基因已成为癌症预防和治疗的一种新的、重要的靶向方法。因此，甲基转移酶抑制剂（MTI）最近成为有前途的化疗或预防药物。强效 MTI 5-aza-2-脱氧胞苷 (5-Azadc) 在体外和体内引起多种肿瘤类型的生长停滞、分化和/或凋亡。本研究表明，低微摩尔浓度的 5-Azadc 可诱导人结直肠癌细胞中 15lipoxygenase-1 (15-LOX-1) 的表达。 15-LOX-1 的表达与 5-Azadc 诱导的 13-S-羟基十八二烯酸水平增加、生长抑制和细胞凋亡相关。此外，通过药理学手段或小干扰RNA特异性抑制15-LOX-1可显着降低5-Azadc诱导的作用。这些新发现首次证明了 MTI 诱导 15-LOX-1 与癌细胞凋亡之间存在机制联系。这一结果对于5-Azadc和其他MTIs预防和治疗结直肠癌的研究具有重要意义，并支持未来MTIs上调15-LOX-1机制的研究。
DNA methylation by DNA methyltransf erases in CpG-rich promoter regions of genes is a well-described component of epigenetic silencing in human cells. Dysregulation of this process in cancer cells may lead to hypermethylation of promoter CpG islands, thus disabling transcription initiation of certain genes, such as tumor suppressor genes. Reversing epigenetic silencing and up-regulating genes involved in preventing or reversing the malignant phenotype has become a new, important targeted approach for cancer prevention and treatment. Therefore, methyltransf erase inhibitors (MTI) have emerged recently as promising chemotherapeutic or preventive agents. The potent MTI 5-aza-2-deoxycytidine (5-Azadc) causes growth arrest, differentiation, and/or apoptosis of many tumor types in vitro and in vivo. The present study shows that low micromolar concentrations of 5-Azadc induce the expression of 15lipoxygenase-1 (15-LOX-1) in human colorectal cancer cells. The expression of 15-LOX-1 correlates with 5-Azadc-induced increases in 13-S-hydroxyoctadecadienoic acid levels, growth inhibition, and apoptosis in these cells. Furthermore, specific inhibition of 15-LOX-1 by pharmacologic means or small interfering RNA significantly reduced the 5-Azadc-induced effects. These novel findings are the first demonstration of a mechanistic link between the induction of 15-LOX-1 by a MTI and apoptosis in cancer cells. This result has important implications for the study of 5-Azadc and other MTIs in the prevention and therapy of colorectal cancer and supports future investigations of the mechanisms by which MTls up-regulate 15-LOX-1.