Targeting nucleolin for better survival in diffuse large B-cell lymphoma

被引:38
作者
Jain, N. [1 ]
Zhu, H. [1 ]
Khashab, T. [1 ,2 ]
Ye, Q. [3 ]
George, B. [3 ]
Mathur, R. [1 ]
Singh, R. K. [1 ]
Berkova, Z. [1 ]
Wise, J. F. [1 ]
Braun, F. K. [1 ]
Wang, X. [1 ]
Patel, K. [3 ]
Xu-Monette, Zy [3 ]
Courty, J. [4 ]
Young, K. H. [3 ]
Sehgal, L. [1 ]
Samaniego, F. [1 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Lymphoma & Myeloma, 7455 Fannin St, Houston, TX 77054 USA
[2] Lankenau Med Ctr, Dept Internal Med, Wynnewood, PA USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA
[4] Univ Paris Est, CNRS, Lab Rech Croissance Cellulaire Reparat & Regenera, Creteil, France
关键词
DNA TOPOISOMERASE-II; DAMAGE RESPONSE; MESSENGER-RNA; BREAST-CANCER; IN-VIVO; PROTEIN; BINDING; APOPTOSIS; EXPRESSION; OVEREXPRESSION;
D O I
10.1038/leu.2017.215
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 (gamma H2AX-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.
引用
收藏
页码:663 / 674
页数:12
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