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Radiosensitization by kinase inhibition revealed by phosphoproteomic analysis of pancreatic cancer cells.
Mol. Cell. Proteomics 19, 1649-1663 (2020)
Publ. Version/Full Text
Research data
DOI
PMC
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers and known for its extensive genetic heterogeneity, high therapeutic resistance, and strong variation in intrinsic radiosensitivity. To understand the molecular mechanisms underlying radioresistance, we screened the phenotypic response of 38 PDAC cell lines to ionizing radiation. Subsequent phosphoproteomic analysis of two representative sensitive and resistant lines led to the reproducible identification of 7,800 proteins and 13,000 phosphorylation sites (p-sites). Approximately 700 p-sites on 400 proteins showed abundance changes after radiation in all cell lines regardless of their phenotypic sensitivity. Apart from recapitulating known radiation response phosphorylation markers such as on proteins involved in DNA damage repair, the analysis uncovered many novel members of a radiation-responsive signaling network that was apparent only at the level of protein phosphorylation. These regulated p-sites were enriched in potential ATM substrates and in vitro kinase assays corroborated 10 of these. Comparing the proteomes and phosphoproteomes of radiosensitive and -resistant cells pointed to additional tractable radioresistance mechanisms involving apoptotic proteins. For instance, elevated NADPH quinine oxidoreductase 1 (NQO1) expression in radioresistant cells may aid in clearing harmful reactive oxygen species. Resistant cells also showed elevated phosphorylation levels of proteins involved in cytoskeleton organization including actin dynamics and focal adhesion kinase (FAK) activity and one resistant cell line showed a strong migration phenotype. Pharmacological inhibition of the kinases FAK by Defactinib and of CHEK1 by Rabusertib showed a statistically significant sensitization to radiation in radioresistant PDAC cells. Together, the presented data map a comprehensive molecular network of radiation-induced signaling, improves the understanding of radioresistance and provides avenues for developing radiotherapeutic strategies.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Cancer Therapeutics ; Enzyme Inhibition ; Kinase Inhibitors ; Kinase Substrates ; Kinases ; Pancreatic Cancer ; Phosphoproteome ; Radioresistance; Focal Adhesion Kinase; Tumor Microenvironment; Phosphorylation Sites; Ionizing-radiation; In-vivo; Dna; Identification; Atm; Activation; Promotes
ISSN (print) / ISBN
1535-9476
e-ISSN
1535-9484
Quellenangaben
Volume: 19,
Issue: 10,
Pages: 1649-1663
Publisher
American Society for Biochemistry and Molecular Biology
Publishing Place
11200 Rockville Pike, Suite 302, Rockville, Md, United States
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Radiation Medicine (IRM)
Grants
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)