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Open AccessArticle

c-Abl Tyrosine Kinase Is Regulated Downstream of the Cytoskeletal Protein Synemin in Head and Neck Squamous Cell Carcinoma Radioresistance and DNA Repair

1
OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
2
Helmholtz-Zentrum Dresden—Rossendorf (HZDR), Institute of Radiooncology—OncoRay, 01328 Dresden, Germany
3
Center for Regenerative Therapies Dresden, Technische Universität Dresden, 01307 Dresden, Germany
4
National Center for Tumor Diseases, Partner Site Dresden, German Cancer Research Center, 69120 Heidelberg, Germany
5
German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, 69120 Heidelberg, Germany
6
Department of Radiotherapy and Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(19), 7277; https://doi.org/10.3390/ijms21197277
Received: 20 July 2020 / Revised: 21 September 2020 / Accepted: 29 September 2020 / Published: 1 October 2020
(This article belongs to the Special Issue Recent Advances in Intermediate Filaments)
The intermediate filament synemin has been previously identified as novel regulator of cancer cell therapy resistance and DNA double strand break (DSB) repair. c-Abl tyrosine kinase is involved in both of these processes. Using PamGene technology, we performed a broad-spectrum kinase activity profiling in three-dimensionally, extracellular matrix grown head and neck cancer cell cultures. Upon synemin silencing, we identified 86 deactivated tyrosine kinases, including c-Abl, in irradiated HNSCC cells. Upon irradiation and synemin inhibition, c-Abl hyperphosphorylation on tyrosine (Y) 412 and threonine (T) 735 was significantly reduced, prompting us to hypothesize that c-Abl tyrosine kinase is an important signaling component of the synemin-mediated radioresistance pathway. Simultaneous targeting of synemin and c-Abl resulted in similar radiosensitization and DSB repair compared with single synemin depletion, suggesting synemin as an upstream regulator of c-Abl. Immunoprecipitation assays revealed a protein complex formation between synemin and c-Abl pre- and post-irradiation. Upon pharmacological inhibition of ATM, synemin/c-Abl protein-protein interactions were disrupted implying synemin function to depend on ATM kinase activity. Moreover, deletion of the SH2 domain of c-Abl demonstrated a decrease in interaction, indicating the dependency of the protein-protein interaction on this domain. Mechanistically, radiosensitization upon synemin knockdown seems to be associated with an impairment of DNA repair via regulation of non-homologous end joining independent of c-Abl function. Our data generated in more physiological 3D cancer cell culture models suggest c-Abl as further key determinant of radioresistance downstream of synemin. View Full-Text
Keywords: ionizing radiation; HNSCC; synemin; c-Abl; DNA repair; zebrafish ionizing radiation; HNSCC; synemin; c-Abl; DNA repair; zebrafish
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MDPI and ACS Style

Deville, S.S.; Delgadillo Silva, L.F.; Vehlow, A.; Cordes, N. c-Abl Tyrosine Kinase Is Regulated Downstream of the Cytoskeletal Protein Synemin in Head and Neck Squamous Cell Carcinoma Radioresistance and DNA Repair. Int. J. Mol. Sci. 2020, 21, 7277.

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