RRC ID 56144
Author Yoshino H, Konno H, Ogura K, Sato Y, Kashiwakura I.
Title Relationship between the Regulation of Caspase-8-Mediated Apoptosis and Radioresistance in Human THP-1-Derived Macrophages.
Journal Int J Mol Sci
Abstract Radiosensitivity varies depending on the cell type; highly differentiated cells typically exhibit greater radioresistance. We recently demonstrated that human macrophages derived from THP-1 monocytic cells, which lack TP53, are highly resistant to radiation-induced apoptosis compared with undifferentiated THP-1 cells. However, the mechanisms by which THP-1 cells acquire radioresistance during differentiation remain unknown. Herein, we investigated the mechanisms by which THP-1-derived macrophages develop p53-independent radioresistance by analyzing DNA damage responses and apoptotic pathways. Analysis of γ-H2AX foci, which indicates the formation of DNA double-strand breaks (DSB), suggested that a capacity to repair DSB of macrophages is comparable to that of radiosensitive THP-1 cells. Furthermore, treatment with inhibitors against DSB repair-related proteins failed to enhance radiation-induced apoptosis in THP-1-derrived macrophages. Analysis of the apoptotic pathways showed that radiosensitive THP-1 cells undergo apoptosis through the caspase-8/caspase-3 cascade after irradiation, whereas this was not observed in the macrophages. Caspase-8 protein expression was lower in macrophages than in THP-1 cells, whereas mRNA expressions were comparable between both cell types. Co-treatment with a proteasome inhibitor and ionizing radiation effectively induced apoptosis in macrophages in a caspase-8-dependent manner. Results suggest that the regulation of caspase-8-mediated apoptosis during differentiation plays a role in the p53-independent radioresistance of THP-1-derived macrophages.
Volume 19(10)
Published 2018-10-13
DOI 10.3390/ijms19103154
PII ijms19103154
PMID 30322167
PMC PMC6214119
MeSH Caspase 8 / genetics Caspase 8 / metabolism* Cell Differentiation Cell Survival / radiation effects DNA Breaks, Double-Stranded DNA Repair Down-Regulation* Gene Expression Regulation, Neoplastic / radiation effects Humans Macrophages / cytology* Macrophages / metabolism Macrophages / pathology Macrophages / radiation effects Radiation Tolerance* THP-1 Cells Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism
IF 4.183
Times Cited 3
Human and Animal Cells THP-1(RCB1189)