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Fractionation-Dependent Radiosensitization by Molecular Targeting of Nek1

Freund, Isabel ; Hehlgans, Stephanie ; Martin, Daniel ; Ensminger, Michael ; Fokas, Emmanouil ; Rödel, Claus ; Löbrich, Markus ; Rödel, Franz (2021):
Fractionation-Dependent Radiosensitization by Molecular Targeting of Nek1. (Publisher's Version)
In: Cells, 9 (5), MDPI, e-ISSN 2073-4409,
DOI: 10.26083/tuprints-00019029,
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Item Type: Article
Origin: Secondary publication service
Status: Publisher's Version
Title: Fractionation-Dependent Radiosensitization by Molecular Targeting of Nek1
Language: English
Abstract:

NIMA (never-in-mitosis gene A)-related kinase 1 (Nek1) is shown to impact on different cellular pathways such as DNA repair, checkpoint activation, and apoptosis. Its role as a molecular target for radiation sensitization of malignant cells, however, remains elusive. Stably transduced doxycycline (Dox)-inducible Nek1 shRNA HeLa cervix and siRNA-transfected HCT-15 colorectal carcinoma cells were irradiated in vitro and 3D clonogenic radiation survival, residual DNA damage, cell cycle distribution, and apoptosis were analyzed. Nek1 knockdown (KD) sensitized both cell lines to ionizing radiation following a single dose irradiation and more pronounced in combination with a 6 h fractionation (3 × 2 Gy) regime. For preclinical analyses we focused on cervical cancer. Nek1 shRNA HeLa cells were grafted into NOD/SCID/IL-2Rγc−/− (NSG) mice and Nek1 KD was induced by Dox-infused drinking water resulting in a significant cytostatic effect if combined with a 6 h fractionation (3 × 2 Gy) regime. In addition, we correlated Nek1 expression in biopsies of patients with cervical cancer with histopathological parameters and clinical follow-up. Our results indicate that elevated levels of Nek1 were associated with an increased rate of local or distant failure, as well as with impaired cancer-specific and overall survival in univariate analyses and for most endpoints in multivariable analyses. Finally, findings from The Cancer Genome Atlas (TCGA) validation cohort confirmed a significant association of high Nek1 expression with a reduced disease-free survival. In conclusion, we consider Nek1 to represent a novel biomarker and potential therapeutic target for drug development in the context of optimized fractionation intervals.

Journal or Publication Title: Cells
Journal volume: 9
Number: 5
Publisher: MDPI
Collation: 16 Seiten
Classification DDC: 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
Divisions: 10 Department of Biology > Radiation Biology and DNA Repair
Date Deposited: 16 Aug 2021 12:19
Last Modified: 16 Aug 2021 12:19
DOI: 10.26083/tuprints-00019029
Corresponding Links:
URN: urn:nbn:de:tuda-tuprints-190292
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/19029
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