Effects of endoplasmic reticulum stress on apoptosis induction in radioresistant macrophages

Yoshino,Hironori; Kumai,Yu; Kashiwakura,Ikuo

doi:10.3892/mmr.2017.6298

Effects of endoplasmic reticulum stress on apoptosis induction in radioresistant macrophages

Authors:
- Hironori Yoshino
- Yu Kumai
- Ikuo Kashiwakura
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Affiliations: Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, Hirosaki, Aomori 036‑8564, Japan, Department of Radiological Technology, Hirosaki University School of Health Sciences, Hirosaki, Aomori 036‑8564, Japan
Published online on: March 8, 2017 https://doi.org/10.3892/mmr.2017.6298
Pages: 2867-2872

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Abstract

Macrophages are important in the host's immune defense against pathogens. However, recent evidence has demonstrated that macrophages are also involved in the development of disease, including cancer. Therefore, it is important to regulate apoptosis in tumor‑related macrophages for effective cancer treatment. In the present study, the effect of endoplasmic reticulum (ER) stress on apoptosis induction was examined in human monocytic cell‑derived macrophages. Radiation therapy in cancer results in irradiating macrophages as well as cancer cells in the tumor microenvironment. Since ER stress has been demonstrated to sensitize cancer cells to radiation, it was hypothesized that ER stress may induce a similar effect in macrophages. Therefore, the effect of combination treatment with ER stress inducers and ionizing radiation on macrophage apoptosis was examined. Treatment of macrophages with ER stress inducers thapsigargin and tunicamycin, enhanced unfolded protein responses, including phosphorylation of eukaryotic initiation factor 2‑α and increased expression of binding immunoglobulin protein. Furthermore, treatment with thapsigargin and tunicamycin induced apoptosis in macrophages compared with untreated cells, although ionizing radiation did not. The thapsigargin-induced apoptosis in macrophages was demonstrated to be caspase‑3‑dependent. Finally, combination treatment with thapsigargin and ionizing radiation, did not result in any significant change in macrophage apoptosis. The present study demonstrated that ER stress regulated apoptosis in radioresistant macrophages and that ionizing radiation had no added effect on ER stress‑induced apoptosis in macrophages.

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1	Murray PJ and Wynn TA: Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol. 11:723–737. 2011. View Article : Google Scholar : PubMed/NCBI
2	Schultze JL, Schmieder A and Goerdt S: Macrophage activation in human diseases. Semin Immunol. 27:249–256. 2015. View Article : Google Scholar : PubMed/NCBI
3	Qian BZ and Pollard JW: Macrophage diversity enhances tumor progression and metastasis. Cell. 141:39–51. 2010. View Article : Google Scholar : PubMed/NCBI
4	Jinushi M, Chiba S, Yoshiyama H, Masutomi K, Kinoshita I, Dosaka-Akita H, Yagita H, Takaoka A and Tahara H: Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc Natl Acad Sci USA. 108:12425–12430. 2011. View Article : Google Scholar : PubMed/NCBI
5	Ostuni R, Kratochvill F, Murray PJ and Natoli G: Macrophages and cancer: From mechanisms to therapeutic implications. Trends Immunol. 36:229–239. 2015. View Article : Google Scholar : PubMed/NCBI
6	Bauer M, Goldstein M, Christmann M, Becker H, Heylmann D and Kaina B: Human monocytes are severely impaired in base and DNA double-strand break repair that renders them vulnerable to oxidative stress. Proc Natl Acad Sci USA. 108:21105–21110. 2011. View Article : Google Scholar : PubMed/NCBI
7	Norbury CJ and Zhivotovsky B: DNA damage-induced apoptosis. Oncogene. 23:2797–2808. 2004. View Article : Google Scholar : PubMed/NCBI
8	Wu J and Kaufman RJ: From acute ER stress to physiological roles of the unfolded protein response. Cell Death Differ. 13:374–384. 2006. View Article : Google Scholar : PubMed/NCBI
9	Naidoo N: Cellular stress/the unfolded protein response: Relevance to sleep and sleep disorders. Sleep Med Rev. 13:195–204. 2009. View Article : Google Scholar : PubMed/NCBI
10	Li J, Lee B and Lee AS: Endoplasmic reticulum stress-induced apoptosis: Multiple pathways and activation of p53-up-regulated modulator of apoptosis (PUMA) and NOXA by p53. J Biol Chem. 281:7260–7270. 2006. View Article : Google Scholar : PubMed/NCBI
11	Contessa JN, Bhojani MS, Freeze HH, Rehemtulla A and Lawrence TS: Inhibition of N-linked glycosylation disrupts receptor tyrosine kinase signaling in tumor cells. Cancer Res. 68:3803–3809. 2008. View Article : Google Scholar : PubMed/NCBI
12	Yamamori T, Meike S, Nagane M, Yasui H and Inanami O: ER stress suppresses DNA double-strand break repair and sensitizes tumor cells to ionizing radiation by stimulating proteasomal degradation of Rad51. FEBS Lett. 587:3348–3353. 2013. View Article : Google Scholar : PubMed/NCBI
13	Sugimoto K, Toyoshima H, Sakai R, Miyagawa K, Hagiwara K, Ishikawa F, Takaku F, Yazaki Y and Hirai H: Frequent mutations in the p53 gene in human myeloid leukemia cell lines. Blood. 79:2378–2383. 1992.PubMed/NCBI
14	Yoshino H, Saitoh T, Kozakai M and Kashiwakura I: Effects of ionizing radiation on retinoic acid-inducible gene-I-like receptors. Biomed Rep. 3:59–62. 2015.PubMed/NCBI
15	Nagelkerke A, Bussink J, van der Kogel AJ, Sweep FC and Span PN: The PERK/ATF4/LAMP3-arm of the unfolded protein response affects radioresistance by interfering with the DNA damage response. Radiother Oncol. 108:415–421. 2013. View Article : Google Scholar : PubMed/NCBI
16	Lee ES, Lee HJ, Lee YJ, Jeong JH, Kang S and Lim YB: Chemical chaperones reduce ionizing radiation-induced endoplasmic reticulum stress and cell death in IEC-6 cells. Biochem Biophys Res Commun. 450:1005–1009. 2014. View Article : Google Scholar : PubMed/NCBI
17	Gotoh T, Oyadomari S, Mori K and Mori M: Nitric oxide-induced apoptosis in RAW 264.7 macrophages is mediated by endoplasmic reticulum stress pathway involving ATF6 and CHOP. J Biol Chem. 277:12343–12350. 2002. View Article : Google Scholar : PubMed/NCBI
18	Devries-Seimon T, Li Y, Yao PM, Stone E, Wang Y, Davis RJ, Flavell R and Tabas I: Cholesterol-induced macrophage apoptosis requires ER stress pathways and engagement of the type A scavenger receptor. J Cell Biol. 171:61–73. 2005. View Article : Google Scholar : PubMed/NCBI
19	Sagara Y and Inesi G: Inhibition of the sarcoplasmic reticulum Ca2+ transport ATPase by thapsigargin at subnanomolar concentrations. J Biol Chem. 266:13503–13506. 1991.PubMed/NCBI
20	Lytton J, Westlin M and Hanley MR: Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. J Biol Chem. 266:17067–17071. 1991.PubMed/NCBI
21	Duksin D and Mahoney WC: Relationship of the structure and biological activity of the natural homologues of tunicamycin. J Biol Chem. 257:3105–3109. 1982.PubMed/NCBI
22	Dubois C, Prevarskaya N and Vanden Abeele F: The calcium-signaling toolkit: Updates needed. Biochim Biophys Acta. 1863:1337–1343. 2016. View Article : Google Scholar : PubMed/NCBI
23	Buckley BJ and Whorton AR: Tunicamycin increases intracellular calcium levels in bovine aortic endothelial cells. Am J Physiol. 273:C1298–C1305. 1997.PubMed/NCBI
24	Suzuki K, Gerelchuluun A, Hong Z, Sun L, Zenkoh J, Moritake T and Tsuboi K: Celecoxib enhances radiosensitivity of hypoxic glioblastoma cells through endoplasmic reticulum stress. Neuro Oncol. 15:1186–1199. 2013. View Article : Google Scholar : PubMed/NCBI
25	Yasui H, Takeuchi R, Nagane M, Meike S, Nakamura Y, Yamamori T, Ikenaka Y, Kon Y, Murotani H, Oishi M, et al: Radiosensitization of tumor cells through endoplasmic reticulum stress induced by PEGylated nanogel containing gold nanoparticles. Cancer Lett. 347:151–158. 2014. View Article : Google Scholar : PubMed/NCBI