Back to Search
Start Over
Head and neck cancer cell radiosensitization upon dual targeting of c-Abl and beta1-integrin.
- Source :
-
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology [Radiother Oncol] 2017 Sep; Vol. 124 (3), pp. 370-378. Date of Electronic Publication: 2017 May 31. - Publication Year :
- 2017
-
Abstract
- Integrin-mediated cell adhesion to extracellular matrix (ECM) critically contributes to cancer cell therapy resistance and DNA double strand break (DSB) repair. c-Abl tyrosine kinase has been linked to both of these processes. Based on our previous findings indicating c-Abl hyperphosphorylation on tyrosine (Y) 412 and threonine (T) 735 upon beta1-integrin inhibition, we hypothesized c-Abl tyrosine kinase as an important mediator of beta1-integrin signaling for radioresistance. In a panel of 8 cell lines from different solid cancer types grown in 3D laminin-rich ECM cultures, we targeted beta1 integrin with AIIB2 (mAb) and c-Abl with Imatinib with and without X-ray irradiation and subsequently examined clonogenic survival, residual DSBs, protein expression and phosphorylation. Single or combined treatment with AIIB2 and Imatinib resulted in cell line-dependent cytotoxicity. Intriguingly, we identified a subgroup of this cell line panel that responded with a higher degree of radiosensitization to AIIB2/Imatinib relative to both single treatments. In this subgroup, we observed a non-statistically significant trend between the radioresponse and phospho-c-Abl Y412. Mechanistically, impairment of DNA repair seems to be associated with radiosensitization upon AIIB2/Imatinib and AIIB2/Imatinib-related radiosensitization could be reduced by exogenous overexpression of either wildtype or constitutively active c-Abl forms relative to controls. Our data generated in more physiological 3D cancer cell culture models suggest c-Abl as further determinant of radioresistance and DNA repair downstream of beta1-integrin. For solid cancers, c-Abl phosphorylation status might be an indicator for reasonable Imatinib application as adjuvant for conventional radio(chemo)therapy.<br /> (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Subjects :
- Carcinoma, Squamous Cell metabolism
Cell Adhesion radiation effects
Cell Line, Tumor
Combined Modality Therapy
DNA Breaks, Double-Stranded
HeLa Cells
Head and Neck Neoplasms metabolism
Humans
Immunoglobulin G immunology
Integrin beta1 immunology
MCF-7 Cells
Molecular Targeted Therapy
Phosphorylation
Radiation Tolerance drug effects
Squamous Cell Carcinoma of Head and Neck
Carcinoma, Squamous Cell drug therapy
Carcinoma, Squamous Cell radiotherapy
Head and Neck Neoplasms drug therapy
Head and Neck Neoplasms radiotherapy
Imatinib Mesylate pharmacology
Immunoglobulin G pharmacology
Integrin beta1 metabolism
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins c-abl antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0887
- Volume :
- 124
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 28578803
- Full Text :
- https://doi.org/10.1016/j.radonc.2017.05.011