RRM1 modulates mitotane activity in adrenal cancer cells interfering with its metabolization
RRM1 modulates mitotane activity in adrenal cancer cells interfering with its metabolization
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DOI：
10.1016/j.mce.2014.11.027
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发表时间：
2015-02-05
影响因子：
4.1
通讯作者：
Terzolo, Massimo
中科院分区：
文献类型：
--
作者：
Germano, Antonina;Rapa, Ida;Terzolo, Massimo
米托坦（o,p'DDD）在肾上腺皮质癌中的抗增殖活性是由其代谢物o，p'DDE和o，p'DDA介导的。我们之前证明了核糖核苷酸还原酶M1（RRM1）表达与o，p'DDD活性之间的功能联系，但其机制尚不清楚。在本研究中，我们评估了RRM1对SW13和H295R细胞中o，p'DDD, o,p'DDE和o，p'DDA的生物利用度和细胞毒活性的影响。在H295R细胞中，米托坦及其代谢物表现出类似的细胞毒性，RRM1的表达不受任何药物的影响。在SW13细胞中，o,p'DDA仅表现出细胞毒活性，不改变RRM1的表达，而o，p'DDE缺乏敏感性与RRM1基因上调有关，正如o，p'DDD已经证明的那样。SW13细胞中RRM1的沉默增加了米托坦向o，p'DDE和o，p'DDA的细胞内转化。这些数据表明，RRM1基因干扰肾上腺皮质癌细胞的米托坦代谢，可能是耐药的机制之一。2014爱思唯尔爱尔兰有限公司版权所有。
The anti-proliferative activity of mitotane (o,p'DDD) in adrenocortical cancer is mediated by its metabolites o,p'DDE and o,p'DDA. We previously demonstrated a functional link between ribonucleotide reductase M1(RRM1) expression and o,p'DDD activity, but the mechanism is unknown. In this study we assessed the impact of RRM1 on the bioavailability and cytotoxic activity of o,p'DDD, o,p'DDE and o,p'DDA in SW13 and H295R cells. In H295R cells, mitotane and its metabolites showed a similar cytotoxicity and RRM1 expression was not influenced by any drug. In SW13 cells, o,p'DDA only showed a cytotoxic activity and did not modify RRM1 expression, whereas the lack of sensitivity to o,p'DDE was associated to RRM1 gene up-modulation, as already demonstrated for o,p'DDD. RRM1 silencing in SW13 cells increased the intracellular transformation of mitotane into o,p'DDE and o,p'DDA. These data demonstrate that RRM1 gene interferes with mitotane metabolism in adrenocortical cancer cells, as a possible mechanisms of drug resistance. (c) 2014 Elsevier Ireland Ltd. All rights reserved.