The BET Inhibitor JQ1 Potentiates the Anticlonogenic Effect of Radiation in Pancreatic Cancer Cells.
The BET Inhibitor JQ1 Potentiates the Anticlonogenic Effect of Radiation in Pancreatic Cancer Cells.
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DOI：
10.3389/fonc.2022.925718
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发表时间：
2022
影响因子：
4.7
通讯作者：
Yoon, Karina J.
中科院分区：
文献类型：
--
作者：
Garcia, Patrick L.;Miller, Aubrey L.;Zeng, Ling;van Waardenburg, Robert C. A. M.;Yang, Eddy S.;Yoon, Karina J.
我们之前报道过BET抑制剂（BETi） JQ1降低DNA修复蛋白RAD51的水平，并且这种降低伴随着DNA损伤水平的增加。基于这些发现，我们假设BETi会增加辐射产生的DNA损伤，并作为放射增敏剂发挥作用。采用体外克隆实验研究JQ1±电离辐射（IR）对三种胰腺癌细胞系的影响。我们采用免疫荧光法评估JQ1±IR对DNA损伤的影响，通过DNA损伤标志物γH2AX的水平来反映，免疫印迹法评估DNA修复蛋白RAD51的水平。我们还比较了这些药物对表达JQ1主要分子靶点（BRD2, BRD4）不同水平的转染物的克隆潜能的影响，以确定这些BET蛋白的水平是否影响对JQ1±IR的敏感性。数据显示，JQ1 + IR比单独使用任何一种方式都更能降低胰腺癌细胞的克隆潜能。这种抗克隆效应与DNA损伤增加和RAD51水平降低有关。此外，较低水平的BRD2或BRD4增加了对JQ1和JQ1 + IR的敏感性，这表明预处理水平的BRD2或BRD4可能预测对BETi或BETi + IR的敏感性。我们认为BETi + IR作为胰腺癌边缘可切除疾病的术前治疗值得评估。
We reported previously that the BET inhibitor (BETi) JQ1 decreases levels of the DNA repair protein RAD51 and that this decrease is concomitant with increased levels of DNA damage. Based on these findings, we hypothesized that a BETi would augment DNA damage produced by radiation and function as a radiosensitizer. We used clonogenic assays to evaluate the effect of JQ1 ± ionizing radiation (IR) on three pancreatic cancer cell lines in vitro. We performed immunofluorescence assays to assess the impact of JQ1 ± IR on DNA damage as reflected by levels of the DNA damage marker γH2AX, and immunoblots to assess levels of the DNA repair protein RAD51. We also compared the effect of these agents on the clonogenic potential of transfectants that expressed contrasting levels of the principle molecular targets of JQ1 (BRD2, BRD4) to determine whether levels of these BET proteins affected sensitivity to JQ1 ± IR. The data show that JQ1 + IR decreased the clonogenic potential of pancreatic cancer cells more than either modality alone. This anticlonogenic effect was associated with increased DNA damage and decreased levels of RAD51. Further, lower levels of BRD2 or BRD4 increased sensitivity to JQ1 and JQ1 + IR, suggesting that pre-treatment levels of BRD2 or BRD4 may predict sensitivity to a BETi or to a BETi + IR. We suggest that a BETi + IR merits evaluation as therapy prior to surgery for pancreatic cancer patients with borderline resectable disease.
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影响因子：
37.3
作者：
Donati B;Lorenzini E;Ciarrocchi A
通讯作者：
Ciarrocchi A
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8.8
作者：
Karakashev S;Zhu H;Yokoyama Y;Zhao B;Fatkhutdinov N;Kossenkov AV;Wilson AJ;Simpkins F;Speicher D;Khabele D;Bitler BG;Zhang R
通讯作者：
Zhang R
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影响因子：
5.2
作者：
Miller AL;Garcia PL;Fehling SC;Gamblin TL;Vance RB;Council LN;Chen D;Yang ES;van Waardenburg RCAM;Yoon KJ
通讯作者：
Yoon KJ
影响因子：
8.8
作者：
Li X;Baek G;Ramanand SG;Sharp A;Gao Y;Yuan W;Welti J;Rodrigues DN;Dolling D;Figueiredo I;Sumanasuriya S;Crespo M;Aslam A;Li R;Yin Y;Mukherjee B;Kanchwala M;Hughes AM;Halsey WS;Chiang CM;Xing C;Raj GV;Burma S;de Bono J;Mani RS
通讯作者：
Mani RS