Capilliposide C from Lysimachia capillipes Restores Radiosensitivity in Ionizing Radiation-Resistant Lung Cancer Cells Through Regulation of ERRFI1/EGFR/STAT3 Signaling Pathway.
Capilliposide C from Lysimachia capillipes Restores Radiosensitivity in Ionizing Radiation-Resistant Lung Cancer Cells Through Regulation of ERRFI1/EGFR/STAT3 Signaling Pathway.
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金钱草中的毛脂苷 C 通过调节 ERRFI1/EGFR/STAT3 信号通路恢复电离抗辐射肺癌细胞的放射敏感性
DOI：
10.3389/fonc.2021.644117
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发表时间：
2021
影响因子：
4.7
通讯作者：
Ma S
中科院分区：
文献类型：
--
作者：
Wu K;Chen X;Feng J;Zhang S;Xu Y;Zhang J;Wu Q;You M;Xia B;Ma S
AIMS放射治疗是肺癌的主要治疗方法。不幸的是，辐射抵抗仍然是肺癌患者面临的主要临床问题。毛细管金钱草(Lysimachia capillipes Capillipode C，LC-C)是一种从LC hemsl中提取的化合物，已在多种癌症中显示出多种抗癌作用。在这里，我们研究了LC-C对肺癌细胞放射敏感性的潜在治疗影响及其潜在的机制。方法以非小细胞肺癌细胞系为研究对象，建立耐电离辐射(IR)肺癌细胞系。RNA-seq分析检测经LC-C处理前后IR耐药肺癌细胞全转录组的变化，并用RT-qPCR验证差异表达基因。克隆形成实验检测LC-C和靶基因ErbB受体反馈抑制物1(ERRFI1)对IR耐药肺癌细胞放射敏感性的影响。用流式细胞仪和γ-H_2AX免疫荧光染色分别检测ERRFI_1对细胞周期分布和DNA损伤修复活性的影响。Western blotting检测相关信号通路的激活情况。通过体内移植瘤实验，观察LC-C和ERRFI1对耐IR肺癌细胞放射敏感性的影响。结果与亲代细胞相比，耐IR肺癌细胞对辐射的抵抗力更强。LC-C在体内外均能显著增强辐射对耐IR肺癌细胞的作用，并通过RNA-seq验证ERRFI1是一个候选下游基因。单独强制表达ERRFI1可显著提高耐IR肺癌细胞的放射敏感性，而沉默ERRFI1可减弱LC-C的放射增敏作用。相应地，LC-C和ERRFI1有效地抑制IR诱导的DNA损伤修复，ERRFI1显著诱导G2/M期检查点停滞。进一步的研究表明，EGFR/STAT3通路的下调在ERRFI1和LC-C的放射增敏中起重要作用。此外，ERRFI1的高表达水平与肺癌患者的高总生存率相关。结论LC-C治疗可能是克服放射抵抗的一种有前景的治疗策略，ERRFI1可能是NSCLC潜在的治疗靶点。
Aims Radiation therapy is used as the primary treatment for lung cancer. Unfortunately, radiation resistance remains to be the major clinic problem for lung cancer patients. Lysimachia capillipes capilliposide C (LC-C), an extract from LC Hemsl, has demonstrated multiple anti-cancer effects in several types of cancer. Here, we investigated the potential therapeutic impacts of LC-C on radiosensitivity in lung cancer cells and their underlying mechanisms. Methods Non-small cell lung cancer cell lines were initially irradiated to generate ionizing radiation (IR)-resistant lung cancer cell lines. RNA-seq analysis was used to examine the whole-transcriptome alteration in IR-resistant lung cancer cells treated with or without LC-C, and the differentially expressed genes with most significance were verified by RT-qPCR. Colony formation assays were performed to determine the effect of LC-C and the target gene ErbB receptor feedback inhibitor 1 (ERRFI1) on radiosensitivity of IR-resistant lung cancer cells. In addition, effects of ERRFI1 on cell cycle distribution, DNA damage repair activity were assessed by flow cytometry and γ-H2AX immunofluorescence staining respectively. Western blotting was performed to identify the activation of related signaling pathways. Tumor xenograft experiments were conducted to observe the effect of LC-C and ERRFI1 on radiosensitivity of IR-resistant lung cancer cells in vivo. Results Compared with parental cells, IR-resistant lung cancer cells were more resistant to radiation. LC-C significantly enhanced the effect of radiation in IR-resistant lung cancer cells both in vitro and in vivo and validated ERRFI1 as a candidate downstream gene by RNA-seq. Forced expression of ERRFI1 alone could significantly increase the radiosensitivity of IR-resistant lung cancer cells, while silencing of ERRFI1 attenuated the radiosensitizing function of LC-C. Accordingly, LC-C and ERRFI1 effectively inhibited IR-induced DNA damage repair, and ERRFI1 significantly induced G2/M checkpoint arrest. Additional investigations revealed that down-regulation of EGFR/STAT3 pathway played an important role in radiosensitization between ERRFI1 and LC-C. Furthermore, the high expression level of ERRFI1 was associated with high overall survival rates in lung cancer patients. Conclusions Treatment of LC-C may serve as a promising therapeutic strategy to overcome the radiation resistance and ERRFI1 may be a potential therapeutic target in NSCLC.
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影响因子：
51.1
作者：
Bradley, Jeffrey D.;Paulus, Rebecca;Komaki, Ritsuko;Masters, Gregory;Blumenschein, George;Schild, Steven;Bogart, Jeffrey;Hu, Chen;Forster, Kenneth;Magliocco, Anthony;Kavadi, Vivek;Garces, Yolanda I.;Narayan, Samir;Iyengar, Puneeth;Robinson, Cliff;Wynn, Raymond B.;Koprowski, Christopher;Meng, Joanne;Beitler, Jonathan;Gaur, Rakesh;Curran, Walter, Jr.;Choy, Hak
通讯作者：
Choy, Hak
影响因子：
15.9
作者：
Oehler, Christoph;von Bueren, Andre O.;Pruschy, Martin
通讯作者：
Pruschy, Martin
影响因子：
20.4
作者：
Goldstraw, Peter;Chansky, Kari;Bolejack, Vanessa
通讯作者：
Bolejack, Vanessa
影响因子：
3.7
作者：
Guerrero-Preston R;Michailidi C;Marchionni L;Pickering CR;Frederick MJ;Myers JN;Yegnasubramanian S;Hadar T;Noordhuis MG;Zizkova V;Fertig E;Agrawal N;Westra W;Koch W;Califano J;Velculescu VE;Sidransky D
通讯作者：
Sidransky D
影响因子：
5.6
作者：
Park H;Jeong YJ;Han NK;Kim JS;Lee HJ
通讯作者：
Lee HJ