ARRB1 enhances the chemosensitivity of lung cancer through the mediation of DNA damage response.
ARRB1 enhances the chemosensitivity of lung cancer through the mediation of DNA damage response.
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ARRB1通过介导DNA损伤反应增强肺癌的化疗敏感性
DOI：
10.3892/or.2016.5337
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发表时间：
2017-02
期刊：
影响因子：
4.2
通讯作者：
Du J
中科院分区：
文献类型：
--
作者：
Shen H;Wang L;Zhang J;Dong W;Zhang T;Ni Y;Cao H;Wang K;Li Y;Wang Y;Du J
ARRB1（也称为 β-arrestin-1）作为多功能接头，有助于调节信号通路。 ARRB1可能参与DNA损伤积累；然而，所涉及的潜在机制尚不清楚。在本研究中，非小细胞肺癌（NSCLC）细胞系（H520和SK-MES-1）被ARRB1质粒或小干扰核糖核酸（siRNA）转染，并接受DNA损伤剂（顺铂和依托泊苷）治疗。使用小鼠异种移植模型来评估 ARRB1 对顺铂体内疗效的影响。本研究共招募了 30 名手术切除的 NSCLC 患者，并进行 qRT-PCR 以确定癌组织与癌旁组织相比的 mRNA 水平。我们的数据表明，DNA 损伤在 ARRB1 敲低细胞中被消除，而在 ARRB1 过表达细胞中增强。与 ARRB1 敲低细胞相比，ARRB1 过表达细胞中的 ATR 和 Chk1 更加激活，随后 H2AX 磷酸化增加。用顺铂处理的 ARRB1 过表达细胞中 DNA 损伤和细胞凋亡增加。这些数据提供了强有力的证据，表明 ARRB1 有助于 NSCLC 对 DNA 损伤剂的反应，并且对于 DNA 损伤反应 (DDR) 至关重要。 ARRB1 可能会增强 DNA 损伤剂在 NSCLC 中的疗效。
ARRB1 (also known as β-arrestin-1) serves as a multifunctional adaptor contributing to the regulation of signaling pathways. ARRB1 may be involved in DNA damage accumulation; however the underlying mechanism involved is unclear. In the present study, non-small cell lung cancer (NSCLC) cell lines (H520 and SK-MES-1) were transfected with ARRB1 plasmids or small interfering ribonucleic acid (siRNA) and received treatment with DNA-damaging agents (cisplatin and etoposide). A mouse xenograft model was used to assess the impact of ARRB1 on the efficacy of cisplatin in vivo. A total of 30 surgically resected NSCLC patients were recruited for the present study and qRT-PCR was performed to determine the mRNA levels in cancer tissues compared with para-carcinoma tissues. Our data showed that DNA damage was abrogated in the ARRB1-knockdown cells and enhanced in the ARRB1-overexpressing cells. ATR and Chk1 were more activated in the ARRB1-overexpressing cells compared to the ARRB1-knockdown cells, followed by increased H2AX phosphorylation. DNA damage and apoptosis were increased in the ARRB1-overexpressing cells treated with cisplatin. These data provided strong evidence that ARRB1 contributes to the response of NSCLC to DNA-damaging agents and is essential for DNA damage response (DDR). ARRB1 may enhance the efficacy of DNA-damaging agents in NSCLC.