Oleandrin induces DNA damage responses in cancer cells by suppressing the expression of Rad51
Oleandrin induces DNA damage responses in cancer cells by suppressing the expression of Rad51
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DOI：
10.18632/oncotarget.10726
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发表时间：
2016-09-13
期刊：
影响因子：
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通讯作者：
Ying, Songmin
中科院分区：
文献类型：
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作者：
Bao, Zhengqiang;Tian, Baoping;Ying, Songmin
夹竹桃素是从夹竹桃的叶和种子中提取的单体化合物。已有文献报道齐墩果苷能有效抑制人癌细胞的生长。然而，齐墩果苷诱导的抗肿瘤作用的具体机制仍很不清楚。基因组不稳定性是肿瘤细胞的主要特征之一，它可以是DNA损伤和肿瘤特异性DNA修复缺陷的共同作用。DNA损伤在肿瘤的发生发展中起着重要作用。事实上，目前的大多数化疗药物都是通过诱导DNA损伤来杀死癌细胞的。在本研究中，我们发现齐墩果苷可以有效地诱导癌细胞的凋亡，并引起快速的DNA损伤反应，表现为核RPA(复制蛋白A，单链DNA结合蛋白)和Upsilon H2AX(DNA双链断裂的标志)焦点形成。有趣的是，参与同源重组(HR)的关键蛋白RAD51的表达被抑制，而XRCC1的表达在齐墩果苷处理的癌细胞中上调。这些结果提示，XRCC1可能在夹竹桃素诱导的DNA损伤修复中起主导作用。总之，齐墩果苷可能通过抑制RAD51的表达而成为一种潜在的抗肿瘤药物。
Oleandrin is a monomeric compound extracted from leaves and seeds of Nerium oleander. It had been reported that oleandrin could effectively inhibit the growth of human cancer cells. However, the specific mechanisms of the oleandrin-induced antitumor effects remain largely unclear. Genomic instability is one of the main features of cancer cells, it can be the combined effect of DNA damage and tumour-specific DNA repair defects. DNA damage plays important roles during tumorigenesis. In fact, most of the current chemotherapy agents were designed to kill cancer cells by inducing DNA damage. In this study, we found that oleandrin was effective to induce apoptosis in cancer cells, and cause rapid DNA damage response, represented by nuclear RPA (Replication Protein A, a single strand DNA binding protein) and Upsilon H2AX(a marker for DNA double strand breaks) foci formation. Interestingly, expression of RAD51, a key protein involved in homologous recombination (HR), was suppressed while XRCC1 was up-regulated in oleandrin treated cancer cells. These results suggested that XRCC1 may play a predominant role in repairing oleandrin-induced DNA damage. Collectively, oleandrin may be a potential anti-tumor agent by suppressing the expression of Rad51.