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Int. J. Mol. Sci. 2018, 19(10), 3154; https://doi.org/10.3390/ijms19103154

Relationship between the Regulation of Caspase-8-Mediated Apoptosis and Radioresistance in Human THP-1-Derived Macrophages

1
Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, 66–1 Hon-cho, Hirosaki, Aomori 036-8564, Japan
2
Department of Radiological Technology, Hirosaki University School of Health Sciences, 66–1 Hon-cho, Hirosaki, Aomori 036-8564, Japan
3
Graduate School of Education, Hirosaki University, 1 Bunkyo-cho, Hirosaki, Aomori 036-8560, Japan
*
Author to whom correspondence should be addressed.
Received: 10 August 2018 / Revised: 3 October 2018 / Accepted: 12 October 2018 / Published: 13 October 2018
(This article belongs to the Collection Radiation Toxicity in Cells)
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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. View Full-Text
Keywords: ionizing radiation; radioresistance; caspase-8; macrophages; apoptosis ionizing radiation; radioresistance; caspase-8; macrophages; apoptosis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Yoshino, H.; Konno, H.; Ogura, K.; Sato, Y.; Kashiwakura, I. Relationship between the Regulation of Caspase-8-Mediated Apoptosis and Radioresistance in Human THP-1-Derived Macrophages. Int. J. Mol. Sci. 2018, 19, 3154.

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