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Title: Targeting Nucleophosmin 1 Represents a Rational Strategy for Radiation Sensitization

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.
Authors:
 [1] ;  [2] ; ;  [1] ; ;  [3] ;  [4] ;  [1] ;  [5] ;  [2] ;  [1]
  1. Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee (United States)
  2. Department of Radiation Oncology, University of Virginia School of Medicine, Charlottesville, Virginia (United States)
  3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas (United States)
  4. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee (United States)
  5. Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas (United States)
Publication Date:
OSTI Identifier:
22420400
Resource Type:
Journal Article
Resource Relation:
Journal Name: International Journal of Radiation Oncology, Biology and Physics; Journal Volume: 89; Journal Issue: 5; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; ANIMAL TISSUES; BIOLOGICAL REPAIR; COLONY FORMATION; DNA; EMBRYOS; FIBROBLASTS; HYPOTHESIS; LUNGS; MICE; NEOPLASMS; RADIOSENSITIVITY; STRAND BREAKS