Targeting nucleolin for better survival in diffuse large B-cell lymphoma.
Targeting nucleolin for better survival in diffuse large B-cell lymphoma.
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DOI：
10.1038/leu.2017.215
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发表时间：
2018-03
期刊：
影响因子：
11.4
通讯作者：
Samaniego F
中科院分区：
文献类型：
--
作者：
Jain N;Zhu H;Khashab T;Ye Q;George B;Mathur R;Singh RK;Berkova Z;Wise JF;Braun FK;Wang X;Patel K;Xu-Monette ZY;Courty J;Young KH;Sehgal L;Samaniego F
蒽环类药物一直是治疗弥漫性大B细胞淋巴瘤(DLBCL)和其他血液病癌症的基石。蒽环类药物清除DLBCL的能力依赖于DNA修复酶复合体拓扑异构酶-II-α(TopIIA)的存在。我们确定核仁素是TopIIA的一种新的结合伙伴。消除核素敏化的DLBCL细胞对TopIIA靶向剂(阿霉素/依托泊苷)的影响。沉默核仁素和用阿霉素攻击DLBCL细胞可增强H_2AX(γ损伤标志物)的磷酸化，并允许DNA片段化。核仁素基因敲除的DLBCL细胞中核仁素表达的重建可阻止TopIIA靶向剂诱导的细胞凋亡。核仁与TopIIA的结合被映射到核仁的RNA结合区3，这种相互作用对于阻断DNA损伤和细胞凋亡是必不可少的。在依托泊苷存在下，核仁沉默降低了TopIIA的降解活性，但促进了TopIIA-DNA可切割复合体的形成。此外，核仁素抑制剂：适体AS1411或核蛋白N6L与阿霉素联合使用可降低DLBCL细胞的存活率。这些发现具有重要的临床意义，因为DLBCL的低核仁素水平与高核仁素水平相比预测了接受R-CHOP治疗的患者90个月的估计存活率为70%与12%(P<；0.0001)。
Anthracyclines have been a cornerstone in the cure of diffuse large B-cell lymphoma (DLBCL) and other hematological cancers. The ability of anthracyclines to eliminate DLBCL depends on the presence of topoisomerase-II-alpha (TopIIA), a DNA repair enzyme complex. We identified nucleolin as a novel binding partner of TopIIA. Abrogation of nucleolin sensitized DLBCL cells to TopIIA targeting agents (doxorubicin/etoposide). Silencing nucleolin and challenging DLBCL cells with doxorubicin enhanced the phosphorylation of H2AX (γH2AX-marker of DNA damage) and allowed DNA fragmentation. Reconstitution of nucleolin expression in nucleolin-knockdown DLBCL cells prevented TopIIA targeting agent-induced apoptosis. Nucleolin binding to TopIIA was mapped to RNA binding domain 3 of nucleolin, and this interaction was essential for blocking DNA damage and apoptosis. Nucleolin silencing decreased TopIIA decatenation activity, but enhanced formation of TopIIA-DNA-cleavable complexes in the presence of etoposide. Moreover, combining nucleolin inhibitors: aptamer AS1411 or nucant N6L with doxorubicin reduced DLBCL cell survival. These findings are of clinical importance because low nucleolin levels versus high nucleolin levels in DLBCL predicted 90 month estimated survival of 70% versus 12% (P<0.0001) of patients treated with R-CHOP based therapy.
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影响因子：
3.8
作者：
Alibolandi, Mona;Ramezani, Mohammad;Hadizadeh, Farzin
通讯作者：
Hadizadeh, Farzin
影响因子：
11.2
作者：
Gilles, Maud-Emmanuelle;Maione, Federica;Cascone, Ilaria
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Cascone, Ilaria
影响因子：
3.6
作者：
Gao, G;Dou, QP
通讯作者：
Dou, QP
DOI：
10.1073/pnas.1306160110
发表时间：
2013-10-15
影响因子：
11.1
作者：
Goldstein, Michael;Derheimer, Frederick A.;Kastan, Michael B.
通讯作者：
Kastan, Michael B.
影响因子：
3.8
作者：
Arriola, Edurne;Rodriguez-Pinilla, Socorro Maria;Reis-Filho, Jorge S.
通讯作者：
Reis-Filho, Jorge S.