IGF-1R inhibition enhances radiosensitivity and delays double-strand break repair by both non-homologous end-joining and homologous recombination.
IGF-1R inhibition enhances radiosensitivity and delays double-strand break repair by both non-homologous end-joining and homologous recombination.
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抑制1型胰岛素样生长因子受体（IGF-1 R）可增强肿瘤细胞对电离辐射的敏感性。目前尚不清楚这种效应是如何介导的，也不清楚这种方法是否可以有效地应用于临床。我们以前表明，IGF-1 R耗竭延迟辐射诱导的DNA双链断裂（DSB）的修复，不太可能完全通过同源重组（HR）修复的减少来解释。目前的研究测试了IGF-1 R抑制诱导涉及非同源末端连接（NHEJ）的修复缺陷的假设。IGF-1 R抑制剂AZ 12253801阻断了细胞存活并使IGF-1 R过表达的鼠成纤维细胞放射增敏，但对同基因IGF-1 R无效细胞无影响，支持IGF-1 R的特异性。IGF-1 R抑制增强DU 145，PC 3和22 Rv 1前列腺癌细胞的放射敏感性，与ATM抑制的效果相当。AZ 12253801处理的DU 145细胞显示γ H2 AX灶延迟消退，在照射后1小时内明显，并持续24小时。相反，IGF-1 R抑制不影响LNCaP-LN 3细胞的放射敏感性或γ H2 AX焦点分辨率，表明放射增敏追踪IGF-1 R影响DSB修复的能力。为了区分对修复与生长和细胞存活反应的影响，我们在DU 145细胞中检测了亚SF 50浓度的AZ 12253801，该浓度对细胞周期分布或凋亡诱导无早期（≤ 48小时）影响。辐照培养物中含有异常的有丝分裂，5天后IGF-1 R抑制细胞表现出增强的辐射诱导的多倍性和核碎片，与进入有丝分裂的后果不完全修复的DNA一致。AZ 12253801放射增敏DNA-PK熟练但不是DNA-PK缺陷的胶质母细胞瘤细胞，并且没有放射增敏DNA-PK抑制的DU 145细胞，这表明在DSB修复的背景下，IGF-1 R在与DNA-PK相同的通路中起作用。最后，在HEK 293报告基因测定中，IGF-1 R抑制减弱了NHEJ和HR的修复。这些数据表明，IGF-1 R通过两种主要的DSB修复途径影响DSB修复，这些发现可能会为这种方法的临床应用提供信息。
Inhibition of type 1 insulin-like growth factor receptor (IGF-1R) enhances tumor cell sensitivity to ionizing radiation. It is not clear how this effect is mediated, nor whether this approach can be applied effectively in the clinic. We previously showed that IGF-1R depletion delays repair of radiation-induced DNA double-strand breaks (DSBs), unlikely to be explained entirely by reduction in homologous recombination (HR) repair. The current study tested the hypothesis that IGF-1R inhibition induces a repair defect that involves non-homologous end-joining (NHEJ). IGF-1R inhibitor AZ12253801 blocked cell survival and radiosensitized IGF-1R over-expressing murine fibroblasts but not isogenic IGF-1R null cells, supporting specificity for IGF-1R. IGF-1R inhibition enhanced radiosensitivity in DU145, PC3 and 22Rv1 prostate cancer cells, comparable to effects of ATM inhibition. AZ12253801-treated DU145 cells showed delayed resolution of γH2AX foci, apparent within 1hr of irradiation and persisting for 24hr. In contrast, IGF-1R inhibition did not influence radiosensitivity or γH2AX focus resolution in LNCaP-LN3 cells, suggesting that radiosensitization tracks with the ability of IGF-1R to influence DSB repair. To differentiate effects on repair from growth and cell survival responses, we tested AZ12253801 in DU145 cells at sub-SF50 concentrations that had no early (≤48hr) effects on cell cycle distribution or apoptosis induction. Irradiated cultures contained abnormal mitoses, and after 5 days IGF-1R inhibited cells showed enhanced radiation-induced polyploidy and nuclear fragmentation, consistent with the consequences of entry into mitosis with incompletely repaired DNA. AZ12253801 radiosensitized DNA-PK proficient but not DNA-PK deficient glioblastoma cells, and did not radiosensitize DNA-PK-inhibited DU145 cells, suggesting that in the context of DSB repair, IGF-1R functions in the same pathway as DNA-PK. Finally, IGF-1R inhibition attenuated repair by both NHEJ and HR in HEK293 reporter assays. These data indicate that IGF-1R influences DSB repair by both major DSB repair pathways, findings that may inform clinical application of this approach.
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影响因子：
64.8
作者：
Jirawatnotai S;Hu Y;Michowski W;Elias JE;Becks L;Bienvenu F;Zagozdzon A;Goswami T;Wang YE;Clark AB;Kunkel TA;van Harn T;Xia B;Correll M;Quackenbush J;Livingston DM;Gygi SP;Sicinski P
通讯作者：
Sicinski P
影响因子：
5.6
作者：
Fabbri, Francesco;Amadori, Dino;Silvestrini, Rosella
通讯作者：
Silvestrini, Rosella
影响因子：
9.7
作者：
Jeon, Jeong Hee;Kim, Se Kyu;Chang, Yoon Soo
通讯作者：
Chang, Yoon Soo
影响因子：
8.8
作者：
Harrington KJ;Billingham LJ;Brunner TB;Burnet NG;Chan CS;Hoskin P;Mackay RI;Maughan TS;Macdougall J;McKenna WG;Nutting CM;Oliver A;Plummer R;Stratford IJ;Illidge T
通讯作者：
Illidge T
影响因子：
82.9
作者：
通讯作者：
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