Tanshinone IIA enhances bystander cell killing of cancer cells expressing Drosophila melanogaster deoxyribonucleoside kinase in nuclei and mitochondria
Tanshinone IIA enhances bystander cell killing of cancer cells expressing Drosophila melanogaster deoxyribonucleoside kinase in nuclei and mitochondria
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丹参酮 IIA 增强旁观者细胞对细胞核和线粒体中表达果蝇脱氧核糖核苷激酶的癌细胞的杀伤作用。
DOI：
10.3892/or.2015.4102
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发表时间：
2015-09-01
期刊：
影响因子：
4.2
通讯作者：
Zheng, Xinyu
中科院分区：
文献类型：
--
作者：
Jiang, Haiyang;Zhao, Lei;Zheng, Xinyu
果蝇多底物脱氧核糖核苷激酶 (Dm-dNK) 的异源表达增加了癌细胞对几种细胞毒性核苷类似物的敏感性。因此，它可以在癌症的基因/化疗联合治疗中用作自杀基因。为了进一步表征这种潜在的自杀基因，我们构建了两种能够在癌细胞中表达 Dm-dNK 的逆转录病毒载体。一种载体含有定位于细胞核的野生型酶。另一个载体含有线粒体定位突变酶，该酶是通过删除核定位信号并将其与细胞色素 c 氧化酶的线粒体输入信号融合而构建的。用重组病毒转导胸苷激酶缺陷型骨肉瘤细胞系。研究了嘧啶核苷类似物 (E)-5-(2-溴乙烯基)-2'-脱氧尿苷和 1-β-D-阿拉伯呋喃胸腺嘧啶存在下的敏感性和旁观者细胞杀伤作用。丹参酮 IIA 是丹参的成分；一种用于治疗心血管疾病的中药。这项研究还探讨了丹参酮 IIA 对旁观者效应的影响及其潜在机制。我们发现骨肉瘤细胞系对核苷类似物的敏感性和旁观者细胞杀伤效率与 Dm-dNK 的亚细胞定位无关。丹参酮IIA对旁观者效应的增强与Cx43和Cx26表达的增加有关。
Heterologous expression of the Drosophila melanogaster multi-substrate deoxyribonucleoside kinase (Dm-dNK) increases the sensitivity of cancer cells to several cytotoxic nucleoside analogs. Thus, it may be used as a suicide gene in combined gene/chemotherapy treatment of cancer. To further characterize this potential suicide gene, we constructed two retroviral vectors that enabled the expression of Dm-dNK in cancer cells. One vector harbored the wild‑type enzyme that localized to the nucleus. The other vector harbored a mitochondrial localized mutant enzyme that was constructed by deleting the nuclear localization signal and fusing it to a mitochondrial import signal of cytochrome c oxidase. A thymidine kinase-deficient osteosarcoma cell line was transduced with the recombinant viruses. The sensitivity and bystander cell killing in the presence of pyrimidine nucleoside analogs (E)-5-(2-bromovinyl)‑2'‑deoxyuridine and 1-β-D-arabinofuranosylthymine were investigated. Tanshinone IIA is a constituent of Danshen; a traditional Chinese medicine used in the treatment of cardiovascular diseases. This study also looked at the influence of Tanshinone IIA on the bystander effect and the underlying mechanisms. We showed that sensitivity of the osteosarcoma cell line to the nucleoside analogs and the efficiency of bystander cell killing were independent of the subcellular localization of Dm-dNK. The enhanced effect of tanshinone IIA on the bystander effect was related to the increased expression of Cx43 and Cx26.