PUBLICATION
c-Abl Tyrosine Kinase Is Regulated Downstream of the Cytoskeletal Protein Synemin in Head and Neck Squamous Cell Carcinoma Radioresistance and DNA Repair
- Authors
- Deville, S.S., Delgadillo Silva, L.F., Vehlow, A., Cordes, N.
- ID
- ZDB-PUB-201007-3
- Date
- 2020
- Source
- International Journal of Molecular Sciences 21(19): (Journal)
- Registered Authors
- Delgadillo Silva, Luis Fernando
- Keywords
- DNA repair, HNSCC, c-Abl, ionizing radiation, synemin, zebrafish
- MeSH Terms
-
- Animals
- Ataxia Telangiectasia Mutated Proteins/genetics*
- Ataxia Telangiectasia Mutated Proteins/metabolism
- Cell Culture Techniques
- Cell Line, Tumor
- Cell Proliferation/radiation effects
- DNA Breaks, Double-Stranded
- DNA Repair*
- DNA, Neoplasm/genetics*
- DNA, Neoplasm/metabolism
- Embryo, Nonmammalian
- Gene Expression Regulation, Neoplastic*
- Head and Neck Neoplasms/genetics
- Head and Neck Neoplasms/metabolism
- Head and Neck Neoplasms/pathology
- Head and Neck Neoplasms/radiotherapy
- Humans
- Intermediate Filament Proteins/antagonists & inhibitors
- Intermediate Filament Proteins/genetics*
- Intermediate Filament Proteins/metabolism
- Phosphorylation
- Protein Binding
- Protein Interaction Domains and Motifs
- Proto-Oncogene Proteins c-abl/genetics*
- Proto-Oncogene Proteins c-abl/metabolism
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Radiation Tolerance/genetics
- Signal Transduction
- Squamous Cell Carcinoma of Head and Neck/genetics
- Squamous Cell Carcinoma of Head and Neck/metabolism
- Squamous Cell Carcinoma of Head and Neck/pathology
- Squamous Cell Carcinoma of Head and Neck/radiotherapy
- X-Rays
- Zebrafish
- PubMed
- 33019757 Full text @ Int. J. Mol. Sci.
Citation
Deville, S.S., Delgadillo Silva, L.F., Vehlow, A., Cordes, N. (2020) c-Abl Tyrosine Kinase Is Regulated Downstream of the Cytoskeletal Protein Synemin in Head and Neck Squamous Cell Carcinoma Radioresistance and DNA Repair. International Journal of Molecular Sciences. 21(19):.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping