Insulin-like growth factor-1 attenuates cisplatin-induced gammaH2AX formation and DNA double-strand breaks repair pathway in non-small cell lung cancer.
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 gammaH2AX, Ser1981-pATM, and Ser428-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 Ser1981-pATM, which is suppressed by cotreatment with IGF-1. In conclusion, cisplatin-induced gammaH2AX 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.
Jeon
Jeong Hee
JH
Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
Kim
Se Kyu
SK
Kim
Hyung Jung
HJ
Chang
Joon
J
Ahn
Chul Min
CM
Chang
Yoon Soo
YS