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Fractionation-dependent radiosensitization by molecular targeting of Nek1

  • 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.
Metadaten
Author:Isabel Freund, Stephanie HehlgansORCiDGND, Daniel MartinORCiD, Michael Ensminger, Emmanouil FokasORCiDGND, Claus RödelORCiDGND, Markus Löbrich, Franz RödelORCiDGND
URN:urn:nbn:de:hebis:30:3-553937
DOI:https://doi.org/10.3390/cells9051235
ISSN:2073-4409
Parent Title (English):Cells
Publisher:MDPI
Place of publication:Basel
Document Type:Article
Language:English
Date of Publication (online):2020/05/16
Date of first Publication:2020/05/16
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/08/13
Tag:Nek1; cervical cancer; colorectal cancer; fractionation; prognostic marker; radiosensitization; xenograft
Volume:9
Issue:5, art. 1235
Page Number:16
First Page:1
Last Page:16
Note:
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
HeBIS-PPN:469520922
Institutes:Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Medizin
Licence (German):License LogoCreative Commons - Namensnennung 4.0