Activation of the AKT/cyclin D1/Cdk4 survival signaling pathway in radioresistant cancer stem cells.
Activation of the AKT/cyclin D1/Cdk4 survival signaling pathway in radioresistant cancer stem cells.
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放射抗性癌症干细胞中 AKT/cyclin D1/Cdk4 存活信号通路的激活。
DOI：
10.1038/oncsis.2012.12
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发表时间：
2012-06-04
期刊：
影响因子：
6.2
通讯作者：
Fukumoto, M.
中科院分区：
文献类型：
--
作者：
Shimura, T.;Noma, N.;Oikawa, T.;Ochiai, Y.;Kakuda, S.;Kuwahara, Y.;Takai, Y.;Takahashi, A.;Fukumoto, M.
肿瘤干细胞具有独特的DNA损伤反应(DDR)、高效的DNA修复和抗凋亡能力，放射抵抗被认为是肿瘤干细胞的内在特征之一，是放射治疗失败的主要原因之一。我们通过长期分次照射82天从HepG2和A172细胞(82FR-31NR细胞)中分离出存活的CSCs。82FR-31NR细胞具有CSC特性，如CSC标志物CD133和ABC转运蛋白(MDR1和BCRP1)的高表达，以及移植到裸鼠体内的高致瘤性。我们分离的CSC的优点是，它们可以在与亲代细胞相同的生长介质中增殖，而不会失去CSC的特性。因此，我们可以分析非干细胞和干细胞的DDR，而不会受到不同培养条件的影响。82FR-31NR细胞对辐射诱导的DNA损伤具有有效的DNA修复作用，并通过激活AKT/Cyclin D1生存信号通路产生辐射抗性。相反，与分离的CSCs相比，亲本细胞中的DNA损伤持续了很长时间。持续的DNA损伤诱导亲本细胞的凋亡，而不激活AKT/细胞周期蛋白D1通路。因此，AKT抑制剂API-2或细胞周期蛋白D1siRNA抑制AKT/细胞周期蛋白D1通路导致82FR-31NR细胞失去有效的DNA修复和放射增敏作用。此外，用其siRNA或CDK4抑制剂敲除CDK4足以抑制CSCs的辐射抗性。在这项研究中，我们提出了一个新发现的关于CSCs辐射反应中AKT/细胞周期蛋白D1/CDK4通路的DDR。分次RT联合靶向AKT/Cyclin D1/CDK4通路的试剂将是治疗CSCs的有效手段。
Radioresistance, which is a major cause of failure of radiotherapy (RT), is proposed as one of the intrinsic characteristics of cancer stem cells (CSCs) whose unique DNA damage response (DDR), efficient DNA repair and resistance to apoptosis are thought to confer the phenotype. We have isolated surviving CSCs by exposure to long-term fractionated radiation for 82 days from HepG2 and A172 cells (82FR-31NR cells). 82FR-31NR cells exhibited CSC properties, such as high expression of CSC marker CD133 and the ABC transporters (MDR1 and BCRP1), and high tumorigenic potential after transplantation into nude mice. The advantage of our isolated CSCs is that they can proliferate in as the same growth medium as that of parental cells without loss of CSC properties. Therefore, we can analyze DDR of non-stem cells and CSCs without any influences caused by different culture conditions. 82FR-31NR cells showed efficient DNA repair of radiation-induced DNA damage and radioresistance with activation of the AKT/cyclin D1 survival signaling pathway. In contrast, DNA damage persisted for a long time after irradiation in parental cells compared with isolated CSCs. Persisted DNA damage induced apoptosis in parental cells without activation of the AKT/cyclin D1 pathway. Therefore, inhibition of the AKT/cyclin D1 pathway by an AKT inhibitor, API-2, or cyclin D1 siRNA resulted in a loss of efficient DNA repair and radiosensitization of 82FR-31NR cells. Furthermore, knockdown of Cdk4 by its siRNA or a Cdk4 inhibitor was sufficient to suppress radioresistance of CSCs. In this study, we present a newly discovered DDR regarding the AKT/cyclin D1/Cdk4 pathway in response to radiation in CSCs. Combination of fractionated RT and reagents targeting the AKT/cyclin D1/Cdk4 pathway to eradicate CSCs would be effective therapeutic modality.
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影响因子：
64.8
作者：
Jirawatnotai S;Hu Y;Michowski W;Elias JE;Becks L;Bienvenu F;Zagozdzon A;Goswami T;Wang YE;Clark AB;Kunkel TA;van Harn T;Xia B;Correll M;Quackenbush J;Livingston DM;Gygi SP;Sicinski P
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作者：
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Heeschen, Christopher
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