Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer in vitro

  • Authors:
    • Hironori Yoshino
    • Miyu Iwabuchi
    • Yuka Kazama
    • Maho Furukawa
    • Ikuo Kashiwakura
  • View Affiliations

  • Published online on: January 26, 2018     https://doi.org/10.3892/ol.2018.7867
  • Pages: 4697-4705
Metrics: HTML 0 views | PDF 0 views     Cited By (CrossRef): 0 citations

Abstract

Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) are pattern‑recognition receptors that recognize pathogen-associated molecular patterns and induce antiviral immune responses. Recent studies have demonstrated that RLR activation induces antitumor immunity and cytotoxicity against different types of cancer, including lung cancer. However a previous report has demonstrated that ionizing radiation exerts a limited effect on RLR in human monocytic cell‑derived macrophages, suggesting that RLR agonists may be used as effective immunostimulants during radiation therapy. However, it is unclear whether ionizing radiation affects the cytotoxicity of RLR agonists against cancer cells. Therefore, in the present study the effects of cotreatment with ionizing radiation and RLR agonists on cytotoxicity against human non‑small cell lung cancer cells A549 and H1299 was investigated. Treatment with RLR agonist poly(I:C)/LyoVec™ [poly(I:C)] exerted cytotoxic effects against human non‑small cell lung cancer. The cytotoxic effects of poly(I:C) were enhanced by cotreatment with ionizing radiation, and poly(I:C) pretreatment resulted in the radiosensitization of non‑small cell lung cancer. Furthermore, cotreatment of A549 and H1299 cells with poly(I:C) and ionizing radiation effectively induced apoptosis in a caspase‑dependent manner compared with treatment with poly(I:C) or ionizing radiation alone. These results indicate that RLR agonists and ionizing radiation cotreatment effectively exert cytotoxic effects against human non‑small cell lung cancer through caspase-mediated apoptosis.

References

1 

Duchen MR: Mitochondria in health and disease: Perspectives on a new mitochondrial biology. Mol Aspects Med. 25:365–451. 2004. View Article : Google Scholar : PubMed/NCBI

2 

Pourcelot M and Arnoult D: Mitochondrial dynamics and the innate antiviral immune response. FEBS J. 281:3791–3802. 2014. View Article : Google Scholar : PubMed/NCBI

3 

Matsumiya T and Stafforini DM: Function and regulation of retinoic acid-inducible gene-I. Crit Rev Immunol. 30:489–513. 2010. View Article : Google Scholar : PubMed/NCBI

4 

Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, Hiiragi A, Dermody TS, Fujita T and Akira S: Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med. 205:1601–1610. 2008. View Article : Google Scholar : PubMed/NCBI

5 

Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, et al: Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 441:101–105. 2006. View Article : Google Scholar : PubMed/NCBI

6 

Li K, Qu S, Chen X, Wu Q and Shi M: Promising targets for cancer immunotherapy: TLRs, RLRs, and STING-mediated innate immune pathways. Int J Mol Sci. 18:pii: E4042017. View Article : Google Scholar

7 

Besch R, Poeck H, Hohenauer T, Senft D, Häcker G, Berking C, Hornung V, Endres S, Ruzicka T, Rothenfusser S and Hartmann G: Proapoptotic signaling induced by RIG-I and MDA-5 results in type I interferon-independent apoptosis in human melanoma cells. J Clin Invest. 119:2399–2411. 2009.PubMed/NCBI

8 

Yuan D, Xia M, Meng G, Xu C, Song Y and Wei J: Anti-angiogenic efficacy of 5′-triphosphate siRNA combining VEGF silencing and RIG-I activation in NSCLCs. Oncotarget. 6:29664–29674. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Yoshino H, Chiba K, Saitoh T and Kashiwakura I: Ionizing radiation affects the expression of Toll-like receptors 2 and 4 in human monocytic cells through c-Jun N-terminal kinase activation. J Radiat Res. 55:876–884. 2014. View Article : Google Scholar : PubMed/NCBI

10 

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. View Article : Google Scholar : PubMed/NCBI

11 

Tsai MF, Wang CC and Chen JJ: Tumour suppressor HLJ1: A potential diagnostic, preventive and therapeutic target in non-small cell lung cancer. World J Clin Oncol. 5:865–873. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Yoshino H, Kumai Y and Kashiwakura I: Effects of endoplasmic reticulum stress on apoptosis induction in radioresistant macrophages. Mol Med Rep. 15:2867–2872. 2017. View Article : Google Scholar : PubMed/NCBI

13 

Fukushi S, Yoshino H, Yoshizawa A and Kashiwakura I: p53-independent structure-activity relationships of 3-ring mesogenic compounds' activity as cytotoxic effects against human non-small cell lung cancer lines. BMC Cancer. 16:5212016. View Article : Google Scholar : PubMed/NCBI

14 

Rogakou EP, Pilch DR, Orr AH, Ivanova VS and Bonner WM: DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 273:5858–5868. 1998. View Article : Google Scholar : PubMed/NCBI

15 

Jacobs JL and Coyne CB: Mechanisms of MAVS regulation at the mitochondrial membrane. J Mol Biol. 425:5009–5019. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Castanier C, Zemirli N, Portier A, Garcin D, Bidère N, Vazquez A and Arnoult D: MAVS ubiquitination by the E3 ligase TRIM25 and degradation by the proteasome is involved in type I interferon production after activation of the antiviral RIG-I-like receptors. BMC Biol. 10:442012. View Article : Google Scholar : PubMed/NCBI

17 

Imaizumi T, Aizawa-Yashiro T, Tsuruga K, Tanaka H, Matsumiya T, Yoshida H, Tatsuta T, Xing F, Hayakari R and Satoh K: Melanoma differentiation-associated gene 5 regulates the expression of a chemokine CXCL10 in human mesangial cells: Implications for chronic inflammatory renal diseases. Tohoku J Exp Med. 228:17–26. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Poeck H, Besch R, Maihoefer C, Renn M, Tormo D, Morskaya SS, Kirschnek S, Gaffal E, Landsberg J, Hellmuth J, et al: 5′-Triphosphate-siRNA: Turning gene silencing and Rig-Iactivation against melanoma. Nat Med. 14:1256–1263. 2008. View Article : Google Scholar : PubMed/NCBI

19 

Li D, Gale RP, Liu Y, Lei B, Wang Y, Diao D and Zhang M: 5′-Triphosphate siRNA targeting MDR1 reverses multi-drug resistance and activates RIG-I-induced immune-stimulatory and apoptotic effects against human myeloid leukaemia cells. Leuk Res. 58:23–30. 2017. View Article : Google Scholar : PubMed/NCBI

20 

Duewell P, Steger A, Lohr H, Bourhis H, Hoelz H, Kirchleitner SV, Stieg MR, Grassmann S, Kobold S, Siveke JT, et al: RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8(+) T cells. Cell Death Differ. 21:1825–1837. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Ranoa DR, Parekh AD, Pitroda SP, Huang X, Darga T, Wong AC, Huang L, Andrade J, Staley JP, Satoh T, et al: Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs. Oncotarget. 7:26496–26515. 2016. View Article : Google Scholar : PubMed/NCBI

22 

Widau RC, Parekh AD, Ranck MC, Golden DW, Kumar KA, Sood RF, Pitroda SP, Liao Z, Huang X, Darga TE, et al: RIG-I-like receptor LGP2 protects tumor cells from ionizing radiation. Proc Natl Acad Sci USA. 111:pp. E484–E491. 2014; View Article : Google Scholar : PubMed/NCBI

23 

Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, Fu YX and Auh SL: The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res. 71:2488–2496. 2011. View Article : Google Scholar : PubMed/NCBI

24 

Schmidberger H, Rave-Fränk M, Lehmann J, Schweinfurth S, Rehring E, Henckel K and Hess CF: The combined effect of interferon beta and radiation on five human tumor cell lines and embryonal lung fibroblasts. Int J Radiat Oncol Biol Phys. 43:405–412. 1999. View Article : Google Scholar : PubMed/NCBI

25 

Lei Y, Moore CB, Liesman RM, O'Connor BP, Bergstralh DT, Chen ZJ, Pickles RJ and Ting JP: MAVS-mediated apoptosis and its inhibition by viral proteins. PLoS One. 4:e54662009. View Article : Google Scholar : PubMed/NCBI

26 

Yu CY, Chiang RL, Chang TH, Liao CL and Lin YL: The interferon stimulator mitochondrial antiviral signaling protein facilitates cell death by disrupting the mitochondrial membrane potential and by activating caspases. J Virol. 84:2421–2431. 2010. View Article : Google Scholar : PubMed/NCBI

27 

El Maadidi S, Faletti L, Berg B, Wenzl C, Wieland K, Chen ZJ, Maurer U and Borner C: A novel mitochondrial MAVS/Caspase-8 platform links RNA virus-induced innate antiviral signaling to Bax/Bak-independent apoptosis. J Immunol. 192:1171–1183. 2014. View Article : Google Scholar : PubMed/NCBI

28 

Verbrugge I, de Vries E, Tait SW, Wissink EH, Walczak H, Verheij M and Borst J: Ionizing radiation modulates the TRAIL death-inducing signaling complex, allowing bypass of the mitochondrial apoptosis pathway. Oncogene. 27:574–584. 2008. View Article : Google Scholar : PubMed/NCBI

29 

Kim MJ, Lee KH and Lee SJ: Ionizing radiation utilizes c-Jun N-terminal kinase for amplification of mitochondrial apoptotic cell death in human cervical cancer cells. FEBS J. 275:2096–2108. 2008. View Article : Google Scholar : PubMed/NCBI

30 

Maier P, Hartmann L, Wenz F and Herskind C: Cellular pathways in response to ionizing radiation and their targetability for tumor radiosensitization. Int J Mol Sci. 17:pii: E1022016. View Article : Google Scholar

31 

Kim JY, An YM, Choi WH, Kim JM, Cho S, Yoo BR, Kang JW, Lee YS, Lee YJ and Cho J: Pro-apoptotic Noxa is involved in ablative focal irradiation-induced lung injury. J Cell Mol Med. 21:711–719. 2017. View Article : Google Scholar : PubMed/NCBI

32 

Liu J, Guo YM, Hirokawa M, Iwamoto K, Ubukawa K, Michishita Y, Fujishima N, Tagawa H, Takahashi N, Xiao W, et al: A synthetic double-stranded RNA, poly I:C, induces a rapid apoptosis of human CD34(+) cells. Exp Hematol. 40:330–341. 2012. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

April 2018
Volume 15 Issue 4

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Yoshino, H., Iwabuchi, M., Kazama, Y., Furukawa, M., & Kashiwakura, I. (2018). Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer in vitro. Oncology Letters, 15, 4697-4705. https://doi.org/10.3892/ol.2018.7867
MLA
Yoshino, H., Iwabuchi, M., Kazama, Y., Furukawa, M., Kashiwakura, I."Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer in vitro". Oncology Letters 15.4 (2018): 4697-4705.
Chicago
Yoshino, H., Iwabuchi, M., Kazama, Y., Furukawa, M., Kashiwakura, I."Effects of retinoic acid-inducible gene-I-like receptors activations and ionizing radiation cotreatment on cytotoxicity against human non-small cell lung cancer in vitro". Oncology Letters 15, no. 4 (2018): 4697-4705. https://doi.org/10.3892/ol.2018.7867