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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • March 2018

Published In

Volume / Issue

  • 32 / 3

Start / End Page

  • 663 - 674

PubMed ID

  • 28690315

Pubmed Central ID

  • 28690315

Electronic International Standard Serial Number (EISSN)

  • 1476-5551

Digital Object Identifier (DOI)

  • 10.1038/leu.2017.215

Language

  • eng

Conference Location

  • England