Skip to main content

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

Publication ,  Journal Article
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 ...
Published in: Leukemia
March 2018

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.

Duke Scholars

Published In

Leukemia

DOI

EISSN

1476-5551

Publication Date

March 2018

Volume

32

Issue

3

Start / End Page

663 / 674

Location

England

Related Subject Headings

  • RNA-Binding Proteins
  • Poly-ADP-Ribose Binding Proteins
  • Phosphoproteins
  • Nucleolin
  • Molecular Targeted Therapy
  • Male
  • Lymphoma, Large B-Cell, Diffuse
  • Immunology
  • Humans
  • Gene Expression
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Jain, N., Zhu, H., Khashab, T., Ye, Q., George, B., Mathur, R., … Samaniego, F. (2018). Targeting nucleolin for better survival in diffuse large B-cell lymphoma. Leukemia, 32(3), 663–674. https://doi.org/10.1038/leu.2017.215

Published In

Leukemia

DOI

EISSN

1476-5551

Publication Date

March 2018

Volume

32

Issue

3

Start / End Page

663 / 674

Location

England

Related Subject Headings

  • RNA-Binding Proteins
  • Poly-ADP-Ribose Binding Proteins
  • Phosphoproteins
  • Nucleolin
  • Molecular Targeted Therapy
  • Male
  • Lymphoma, Large B-Cell, Diffuse
  • Immunology
  • Humans
  • Gene Expression