Insulin-like growth factor-1 attenuates cisplatin-induced γH2AX formation and DNA double-strand breaks repair pathway in non-small cell lung cancer
Insulin-like growth factor-1 attenuates cisplatin-induced γH2AX formation and DNA double-strand breaks repair pathway in non-small cell lung cancer
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DOI：
10.1016/j.canlet.2008.07.011
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发表时间：
2008-12-18
期刊：
影响因子：
9.7
通讯作者：
Chang, Yoon Soo
中科院分区：
文献类型：
--
作者：
Jeon, Jeong Hee;Kim, Se Kyu;Chang, Yoon Soo
由于胰岛素样生长因子-1（IGF-1）通过形成铂-DNA加合物来抵消顺铂诱导DNA损伤和细胞死亡的抗肿瘤作用，我们研究了IGF-1对顺铂诱导的DNA双链断裂（DSB）修复系统的影响。用从顺铂衍生的回收的IGF-1处理的NCI-H1299和H460非小细胞肺癌（NSCLC）细胞抑制增殖和凋亡。在彗星试验中，IGF-1共处理降低了尾长并抑制了组蛋白H2 AX在Ser 139处的磷酸化，表明IGF-1减弱了顺铂诱导的DNA损伤。与IGF-1共治疗减弱了共济失调毛细血管扩张症突变（ATM）在Ser 1981的磷酸化，ATM-Rad 3相关（ATR）在Ser 428和随后的磷酸化的Chk 2，Chk 1，和p53也减少IGF-1。另一方面，用AG 1024或胰岛素受体底物-1（IRS-1）（IGF系统的主要衔接分子）的siRNA抑制IGF系统，增强顺铂诱导的γ H2 AX、Ser（1981）-pATM和Ser（428）-pATR的产生。ATM在组蛋白H2 AX和Chk 2的Thr 68磷酸化中起重要作用，在顺铂的影响下与IRS-1强烈结合，并且这种相互作用被IGF-1部分抑制。免疫细胞化学显示，顺铂诱导IRS-1与Ser（1981）-pATM的核转位，这被IGF-1的共同处理抑制。总之，顺铂诱导的γ H2 AX形成、DNA DSB修复和损伤检查点途径被IGF-1抑制。顺铂衍生ATM和IRS-1之间的相互作用，其被IGF-1抑制。调节IGF-1系统的生物活性可能是一种有前途的方式，提高了常规化疗的反应率。(c)2008爱思唯尔爱尔兰有限公司保留所有权利。
Because insulin-like growth factor-1 (IGF-1) counteracts the anti-neoplastic effect of cisplatin that induces DNA damage and cell death through the formation of platinum-DNA adducts, we investigated the effects of IGF-1 on the DNA double-strand breaks (DSBs) repair system induced by cisplatin. NCI-H1299 and H460 non-small cell lung cancer (NSCLC) cells treated with IGF-1 recovered from cisplatin-derived inhibited proliferation and apoptosis. Decreased tail length in comet assay and suppressed phosphorylation of histone H2AX at Ser139 with IGF-1 cotreatment indicates that IGF-1 attenuates cisplatin-induced DNA damage. Cotreatment with IGF-1 attenuates phosphorylation of ataxia-telangiectasia mutated (ATM) at Ser1981, and ATM-Rad3-related (ATR) at Ser428 and subsequent phosphorylation of Chk2, Chk1, and p53 also dwindled by IGF-1. On the other hand, suppression of the IGF system with AG1024 or siRNA of insulin receptor substrate-1 (IRS-1), a major adaptor molecule of the IGF system, augmented cisplatin-induced gamma H2AX, Ser(1981)-pATM, and Ser(428)-pATR generation. ATM, which plays an important role in the phosphorylation of histone H2AX and Chk2 at Thr68, strongly binds with IRS-1 under the influence of cisplatin, and the interaction was partially inhibited by IGF-1. Immunocytochemistry revealed that cisplatin induces nuclear translocation of IRS-1 with Ser(1981)-pATM, which is suppressed by cotreatment with IGF-1. In conclusion, cisplatin-induced gamma H2AX formation, DNA DSBs repair, and damage checkpoint pathway is inhibited by IGF-1. Cisplatin derives interaction between ATM and IRS-1, which is suppressed by IGF-1. Modulation of biologic activity of the IGF-1 system could be a promising modality that raises the response rate of conventional chemotherapy. (c) 2008 Elsevier Ireland Ltd. All rights reserved.