Effects of RIalpha overexpression on cisplatin sensitivity in human ovarian carcinoma cells.
Effects of RIalpha overexpression on cisplatin sensitivity in human ovarian carcinoma cells.
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RIα过表达对人卵巢癌细胞顺铂敏感性的影响。
DOI：
10.1006/bbrc.1998.9223
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发表时间：
1998
影响因子：
3.1
通讯作者：
Chin,KV
中科院分区：
文献类型：
--
作者：
Cvijic,ME;Chin,KV
我们的实验室已经发现，中国仓鼠卵巢（CHO）和小鼠Y1肾上腺皮质癌PKA突变体与缺陷的R亚基，但不改变C亚基，表现出增加顺铂以及其他DNA损伤剂的耐药性。RIα突变体的耐药机制可能与其对顺铂损伤的DNA的识别能力增强以及蛋白质与DNA损伤的结合，从而增强DNA的修复有关。这些数据表明RIα突变可能通过影响DNA修复活性而赋予顺铂耐药性。在本研究中，我们在人卵巢癌A2780细胞中过表达RIα，以证明RIα可以调节细胞对顺铂的敏感性。逆转录病毒感染的A2780细胞过度表达野生型RIα cDNA显示出4 - 8倍的敏感性顺铂相比，父母的细胞。RIα在A2780的CP 70顺铂耐药衍生物中的过表达也增加了这些细胞对顺铂的敏感性。因此，PKA的RIα亚基的表达增强使细胞对这种DNA损伤剂的细胞毒性作用敏感。这些数据表明，RIα可能直接作用，独立于C亚基，影响细胞对顺铂的敏感性。因此，通过药物调节RIα表达或其功能状态可能潜在地逆转肿瘤中的顺铂耐药性。
Our laboratory has found that Chinese hamster ovary (CHO) and mouse Y1 adrenocortical carcinoma PKA mutants with a defective R subunit, but not altered C subunits, exhibit increased resistance to cisplatin as well as other DNA-damaging agents. The mechanism of resistance may be associated with increased recognition of the cisplatin-damaged DNA and protein binding to the DNA lesion, thus enhancing DNA repair in the RIα mutants. These data suggest that mutation of RIα may confer resistance to cisplatin by affecting DNA repair activity. In the present study, we overexpressed RIα in human ovarian carcinoma A2780 cells to demonstrate that RIα can modulate cellular sensitivity to cisplatin. Retroviral-infected A2780 cells overexpressing wild-type RIα cDNA displayed a four- to eightfold greater sensitivity to cisplatin compared with parental cells. Overexpression of RIα in the CP70 cisplatin-resistant derivative of A2780 also increased the sensitivity of these cells to cisplatin. Therefore, enhanced expression of the RIα subunit of PKA sensitizes cells to the cytotoxic effects of this DNA-damaging agent. These data suggest that RIα may act directly, independent of the C subunit, to influence cellular sensitivity to cisplatin. Therefore, modulation of RIα expression or its functional status by pharmacological agents may potentially reverse cisplatin resistance in tumors.