Targeting Nucleophosmin 1 Represents a Rational Strategy for Radiation Sensitization
| Autor: | Mouadh Benamar, Soumya Sasi, Michael L. Freeman, Konjeti R. Sekhar, Narsimha Reddy Penthala, Stephen R. Hann, Ramesh Balusu, Ling Geng, Peter A. Crooks, Amudhan Venkateswaran, Tarek Abbas |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Radiation-Sensitizing Agents
Cancer Research NPM1 Indoles Lung Neoplasms DNA Repair DNA repair RAD51 Mice Nude Radiation Tolerance Article Histones Mice Radiation sensitivity Carcinoma Non-Small-Cell Lung Tumor Cells Cultured Animals Humans Medicine DNA Breaks Double-Stranded Radiology Nuclear Medicine and imaging Molecular Targeted Therapy Radiosensitivity Nucleophosmin Radiation Tissue microarray biology business.industry Nuclear Proteins Fibroblasts Neoplasm Proteins Mice Inbred C57BL Histone Oncology Tissue Array Analysis Barbiturates Cancer research biology.protein Rad51 Recombinase business |
| Zdroj: | International Journal of Radiation Oncology*Biology*Physics. 89:1106-1114 |
| ISSN: | 0360-3016 |
| DOI: | 10.1016/j.ijrobp.2014.04.012 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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