Chemotherapy and Radiotherapy Downregulate the Activity and Expression of DNA Methyltransferase and Enhance Bcl-2/E1B-19-kDa Interacting Protein-3-Induced Apoptosis in Human Colorectal Cancer Cells
Chemotherapy and Radiotherapy Downregulate the Activity and Expression of DNA Methyltransferase and Enhance Bcl-2/E1B-19-kDa Interacting Protein-3-Induced Apoptosis in Human Colorectal Cancer Cells
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DOI：
10.1159/000345916
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发表时间：
2012-01-01
期刊：
影响因子：
3.3
通讯作者：
Wang, Wei
中科院分区：
文献类型：
--
作者：
Deng, Qian;Huang, Chun-mei;Wang, Wei
BCL-2/E1B 19-kDa相互作用蛋白3(BNIP3)是一种促凋亡蛋白，由于BNIP3基因启动子DNA被DNA甲基转移酶(DNMT)甲基化，BNIP3在结直肠癌细胞中的表达水平较低。众所周知，化疗和放射治疗通过诱导肿瘤细胞凋亡来抑制结直肠癌。然而，化疗和放疗诱导结直肠癌细胞凋亡的分子机制还不是很清楚。在本研究中，我们观察到BNIP3在结肠癌细胞中的表达水平在体外经治疗药物和放射治疗后显著增加。术前同时接受化疗的患者结直肠癌组织中BNIP3蛋白水平显著高于单纯手术患者。此外，化疗药物和放射治疗显著降低了DNMT1的表达水平和酶活性。DNMT1的表达水平和活性与化疗药物和放疗后BNIP3的表达水平呈负相关。与BNIP3表达增加一致，化疗药物和放射诱导结肠癌细胞凋亡呈剂量依赖关系。根据这些观察，我们得出结论，化疗和放疗抑制DNMT1的表达，从而上调BNIP3的表达，促进结直肠癌细胞的凋亡。而且，BNIP3可能在caspase依赖的细胞凋亡通路中发挥作用，主要是在化疗和放射治疗过程中。版权所有(C)2013 S.Karger AG，巴塞尔
Bcl-2/E1B 19-kDa interacting protein 3 (BNIP3) is a proapoptotic protein whose expression level is often low in colorectal cancer (CRC) cells due to the BNIP3 gene promoter DNA methylation by DNA methyltransferase (DNMT). It is known that chemotherapy and radiotherapy suppress CRC through inducing tumor apoptosis. However, the molecular mechanisms underlying chemotherapy and radiotherapy-induced apoptosis of CRC cells are not well defined. In this study, we observed that the expression level of BNIP3 in colon cancer cells was significantly increased by treatment with therapeutic agents and radiation in vitro. The BNIP3 protein level in CRC tissues from patients who received preoperative concurrent chemotherapy was significantly higher than in those who received surgery alone. Furthermore, treatment with chemotherapeutic agents and radiation significantly decreased the DNMT1 expression level and enzymatic activity. Both expression level and activity of DNMT1 were inversely correlated with the expression level of BNIP3 in colon carcinoma cells after treatment with chemotherapeutic agents and radiation. Consistent with increased BNIP3 expression, chemotherapeutic agents and radiation induced colon carcinoma cell apoptosis in a dose-dependent manner. Based on these observations, we conclude that chemotherapy and radiotherapy inhibit DNMT1 expression to up-regulate BNIP3 expression to promote CRC cell apoptosis. And, BNIP3 may play a role in the caspase-dependent apoptosis pathways, mainly during treatment with chemotherapy and radiotherapy. Copyright (C) 2013 S. Karger AG, Basel