TY  - JOUR
A1  - Freund, Isabel
A1  - Hehlgans, Stephanie
A1  - Martin, Daniel
A1  - Ensminger, Michael
A1  - Fokas, Emmanouil
A1  - Rödel, Claus
A1  - Löbrich, Markus
A1  - Rödel, Franz
T1  - Fractionation-dependent radiosensitization by molecular targeting of Nek1
T2  - Cells
N2  - 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.
KW  - Nek1
KW  - cervical cancer
KW  - colorectal cancer
KW  - fractionation
KW  - radiosensitization
KW  - xenograft
KW  - prognostic marker
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/55393
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-553937
SN  - 2073-4409
N1  - 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/).
VL  - 9
IS  - 5, art. 1235
SP  - 1
EP  - 16
PB  - MDPI
CY  - Basel
ER  -