Cisplatin resistance by induction of aldo-keto reductase family 1 member C2 in human bladder cancer cells.
Cisplatin resistance by induction of aldo-keto reductase family 1 member C2 in human bladder cancer cells.
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DOI：
10.3892/ol.2013.1768
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发表时间：
2014-03
期刊：
影响因子：
2.9
通讯作者：
Yokoyama M
中科院分区：
文献类型：
--
作者：
Shirato A;Kikugawa T;Miura N;Tanji N;Takemori N;Higashiyama S;Yokoyama M
顺铂是目前治疗膀胱癌最有效的抗肿瘤药物。为了阐明膀胱癌顺铂耐药的机制，本研究利用人膀胱癌细胞系研究了醛酮还原酶家族1成员C2 （AKR1C2）蛋白在化疗耐药中的作用。利用人HT1376膀胱癌细胞株和顺铂耐药HT1376- cisr亚系研究了AKR1C2在化疗耐药中的作用。AKR1C2在HT1376-CisR细胞中表达，而在亲本细胞中不表达。研究了小干扰（si） rna和靶向AKR1C2的抑制剂的作用，以确定是否可以通过阻断AKR1C2的表达或功能来挽救顺铂敏感性。5β-胆酸沉默AKR1C2 mRNA或抑制AKR1C2可导致顺铂暴露后细胞存活率降低。采用2,7-二氯二氢荧光素（H2DCFDA）荧光探针测定细胞内活性氧（ROS）的积累。顺铂暴露增加HT1376细胞内ROS水平呈剂量依赖性。HT1376- cisr细胞中的ROS水平明显低于HT1376细胞，敲低AKR1C2 mRNA可显著恢复ROS水平。顺铂暴露并未增加HT1376- cisr细胞的细胞内ROS，尽管顺铂暴露后HT1376细胞内ROS水平升高。在HT1376-CisR细胞中，AKR1C2 mRNA的沉默恢复了ROS对顺铂和甲萘醌作为氧化应激源的增加反应。美那酮具有氧化应激源的功能。在HT1376-CisR细胞中，AKR1C2 mRNA的沉默恢复了对顺铂和甲萘醌增加的ROS反应。这些结果表明，在人膀胱癌细胞中诱导AKR1C2通过抗氧化作用有助于顺铂耐药的发展。本研究结果提示，AKR1C2可能是恢复顺铂耐药的有效分子靶点。
Cisplatin is currently the most effective anti-tumor agent available against bladder cancer. To clarify the mechanism underlying cisplatin resistance in bladder cancer, the present study examined the role of the aldo-keto reductase family 1 member C2 (AKR1C2) protein on chemoresistance using a human bladder cancer cell line. The function of AKR1C2 in chemoresistance was studied using the human HT1376 bladder cancer cell line and the cisplatin-resistant HT1376-CisR subline. AKR1C2 was expressed in HT1376-CisR cells, but not in the parental cells. The effect of small interfering (si) RNAs and an inhibitor targeting AKR1C2 was examined to determine whether cisplatin sensitivity can be rescued by blocking AKR1C2 expression or function. Silencing of AKR1C2 mRNA or inhibition of AKR1C2 by 5β-cholanic acid resulted in a decrease in the survival of cells following cisplatin exposure. Intracellular accumulation of reactive oxygen species (ROS) was determined using a 2,7-dichlorodihydrofluorescein diacetate (H2DCFDA) fluorescent probe. Cisplatin exposure increased the level of intracellular ROS in HT1376 cells in a dose-dependent manner. The ROS levels in HT1376-CisR cells were significantly lower than those in HT1376 cells and knockdown of AKR1C2 mRNA significantly restored ROS levels. Cisplatin exposure did not increase intracellular ROS in HT1376-CisR cells, although the level of intracellular ROS increased in HT1376 cells following cisplatin exposure. Silencing of AKR1C2 mRNA restored the ROS increase response to cisplatin and menadione as an oxidative stressor in HT1376-CisR cells. Menadione has the function of an oxidative stressor. The silencing of AKR1C2 mRNA restored the increased ROS response to cisplatin and menadione in HT1376-CisR cells. These results indicate that induction of AKR1C2 in human bladder cancer cells aids in the development of cisplatin resistance through antioxidative effects. The results of this study indicate that AKR1C2 may be an effective molecular target for restoring cisplatin resistance.
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影响因子：
5.8
作者：
Hour TC;Lai YL;Kuan CI;Chou CK;Wang JM;Tu HY;Hu HT;Lin CS;Wu WJ;Pu YS;Sterneck E;Huang AM
通讯作者：
Huang AM
影响因子：
4.6
作者：
Chow, KC;Lu, MP;Wu, MT
通讯作者：
Wu, MT
影响因子：
45.3
作者：
von der Maase, H;Hansen, SW;Conte, PF
通讯作者：
Conte, PF
DOI：
10.1016/0192-0561(86)90006-8
发表时间：
1986-01-01
期刊：
INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY
影响因子：
--
作者：
SODHI, A;GUPTA, P
通讯作者：
GUPTA, P
影响因子：
7.3
作者：
Tardito, Saverio;Bussolati, Ovidio;Marchio, Luciano
通讯作者：
Marchio, Luciano