期刊
CANCER LETTERS
卷 272, 期 2, 页码 232-241出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2008.07.011
关键词
Non-small cell lung cancer; Cisplatin; Insulin-like growth factor-1; DNA DSBs repair system; Damaged-DNA checkpoint; Ataxia-telangiectasia mutated; ATM-Rad3-related; DNA-dependent protein kinase; gamma H2AX
类别
资金
- government of Republic of Korea [KRF-2007-331-E00079]
- Brain Korea 21 Project for Medical Science
- Yonsei University College of Medicine
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.
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