Targeting nucleophosmin 1 represents a rational strategy for radiation sensitization.

Sekhar KR, Benamar M, Venkateswaran A, Sasi S, Penthala NR, Crooks PA, Hann SR, Geng L, Balusu R, Abbas T, Freeman ML
Int J Radiat Oncol Biol Phys. 2014 89 (5): 1106-1114

PMID: 25035215 · PMCID: PMC4105849 · DOI:10.1016/j.ijrobp.2014.04.012

PURPOSE - To test the hypothesis that small molecule targeting of nucleophosmin 1 (NPM1) represents a rational approach for radiosensitization.

METHODS AND MATERIALS - Wilde-type and NPM1-deficient mouse embryo fibroblasts (MEFs) were used to determine whether radiosensitization produced by the small molecule YTR107 was NPM1 dependent. The stress response to ionizing radiation was assessed by quantifying pNPM1, γH2AX, and Rad51 foci, neutral comet tail moment, and colony formation. NPM1 levels in a human-derived non-small-cell lung cancer (NSCLC) tissue microarray (TMA) were determined by immunohistochemistry. YTR107-mediated radiosensitization was assessed in NSCLC cell lines and xenografts.

RESULTS - Use of NPM1-null MEFs demonstrated that NPM1 is critical for DNA double- strand break (DSB) repair, that loss of NPM1 increases radiation sensitivity, and that YTR107-mediated radiosensitization is NPM1 dependent. YTR107 was shown to inhibit NPM1 oligomerization and impair formation of pNPM1 irradiation-induced foci that colocalized with γH2AX foci. Analysis of the TMA demonstrated that NPM1 is overexpressed in subsets of NSCLC. YTR107 inhibited DNA DSB repair and radiosensitized NSCLC lines and xenografts.

CONCLUSIONS - These data demonstrate that YTR107-mediated targeting of NPM1 impairs DNA DSB repair, an event that increases radiation sensitivity.

Copyright © 2014 Elsevier Inc. All rights reserved.

MeSH Terms (21)

Animals Barbiturates Carcinoma, Non-Small-Cell Lung DNA Breaks, Double-Stranded DNA Repair Fibroblasts Histones Humans Indoles Lung Neoplasms Mice Mice, Inbred C57BL Mice, Nude Molecular Targeted Therapy Neoplasm Proteins Nuclear Proteins Rad51 Recombinase Radiation-Sensitizing Agents Radiation Tolerance Tissue Array Analysis Tumor Cells, Cultured

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