Depleting Mirk Kinase Increases Cisplatin Toxicity in Ovarian Cancer Cells.
Depleting Mirk Kinase Increases Cisplatin Toxicity in Ovarian Cancer Cells.
复制标题
DOI：
10.1177/1947601910377644
复制
发表时间：
2010-08-01
期刊：
影响因子：
--
通讯作者：
Friedman E
中科院分区：
文献类型：
--
作者：
Hu J;Friedman E
以顺铂为基础的治疗方案是卵巢上皮癌的标准治疗方案。由于已知顺铂会增加细胞内毒性活性氧（ROS）水平，因此通过靶向卵巢癌中上调的抗氧化基因，进一步增加顺铂升高的ROS水平，可能会导致癌细胞中顺铂毒性的选择性增加。丝氨酸/苏氨酸激酶Mirk/dyrk 1B是一种转录共激活因子，可增加卵巢癌细胞中抗氧化基因超氧化物歧化酶2和亚铁氧化酶的表达。结果，Mirk的消耗增加了4种卵巢癌细胞系中每一种细胞的ROS水平。Mirk消耗平均仅约4倍，但与顺铂治疗组合使得低水平的药物能够在SKOV 3和TOV 21 G卵巢癌细胞中将ROS增加至毒性水平。通过用N-乙酰半胱氨酸处理来降低ROS水平限制顺铂毒性，导致更高的细胞数量和减少的凋亡蛋白PARP和半胱天冬酶3的切割。Mirk还被证明通过诱导细胞周期蛋白D1的蛋白质水解来阻止细胞处于G1期。Mirk缺失增加了4个卵巢癌细胞系中的3个细胞周期蛋白D1水平，这意味着一些Mirk缺失的细胞可以更容易地进入周期，潜在地增加了它们对顺铂的敏感性。由于Mirk在人类卵巢癌的大子集中上调，但在大多数正常组织中以低水平表达，并且Mirk的胚胎敲除导致存活和可生育的小鼠，靶向Mirk可能使卵巢癌对较低水平的顺铂敏感，同时保留正常组织。
Cisplatin-based regimens are the standard of care for epithelial carcinoma of the ovary. Since cisplatin is known to increase intracellular levels of toxic reactive oxygen species (ROS), an increase in cisplatin toxicity selectively in cancer cells could result from further increasing the cisplatin-elevated ROS levels by targeting antioxidant genes upregulated in ovarian cancers. The serine/threonine kinase Mirk/dyrk1B is a transcriptional co-activator which increased the expression of the antioxidant genes superoxide dismutase 2 and ferroxidase in ovarian cancer cells. As a result, depletion of Mirk increased cellular ROS levels in each of 4 ovarian cancer cell lines. Mirk depletion averaged only about 4 fold, yet combined with cisplatin treatment enabled low levels of drug to increase ROS to toxic levels in both SKOV3 and TOV21G ovarian cancer cells. Lowering ROS levels by treatment with N-acetyl cysteine limited cisplatin toxicity, resulting in higher cell numbers and decreased cleavage of the apoptotic proteins PARP and caspase 3. Mirk has also been shown to block cells in G1 by inducing proteolysis of cyclin D1. Mirk depletion increased cyclin D1 levels in 3 of 4 ovarian cancer cell lines, implying that some Mirk depleted cells could more readily enter cycle, potentially increasing their sensitivity to cisplatin. Since Mirk is upregulated in a large subset of human ovarian cancers, but is expressed at low levels in most normal tissues, and embryonic knockout of Mirk results in viable and fertile mice, targeting Mirk may sensitize ovarian cancers to lower levels of cisplatin, while sparing normal tissues.