Iodine‑125 seed radiation induces ROS‑mediated apoptosis, autophagy and paraptosis in human esophageal squamous cell carcinoma cells

Wang,Chao; Li,Tian‑Kuan; Zeng,Chu‑Hui; Fan,Rui; Wang,Yong; Zhu,Guang‑Yu; Guo,Jin‑He

doi:10.3892/or.2020.7576

Iodine‑125 seed radiation induces ROS‑mediated apoptosis, autophagy and paraptosis in human esophageal squamous cell carcinoma cells

Authors:
- Chao Wang
- Tian‑Kuan Li
- Chu‑Hui Zeng
- Rui Fan
- Yong Wang
- Guang‑Yu Zhu
- Jin‑He Guo
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Affiliations: Jiangsu Key Laboratory of Molecular and Functional Imaging, Medical School, Southeast University, Nanjing, Jiangsu 210009, P.R. China, Center of Interventional Radiology and Vascular Surgery, Department of Radiology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, P.R. China
Published online on: April 3, 2020 https://doi.org/10.3892/or.2020.7576
Pages: 2028-2044
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Iodine‑125 (125I) seed brachytherapy has been proven to be a safe and effective treatment for advanced esophageal cancer; however, the mechanisms underlying its actions are not completely understood. In the present study, the anti‑cancer mechanisms of 125I seed radiation in human esophageal squamous cell carcinoma (ESCC) cells (Eca‑109 and KYSE‑150) were determined, with a particular focus on the mode of cell death. The results showed that 125I seed radiation significantly inhibited cell proliferation, and induced DNA damage and G2/M cell cycle arrest in both ESCC cell lines. 125I seed radiation induced cell death through both apoptosis and paraptosis. Eca‑109 cells were primarily killed by inducing caspase‑dependent apoptosis, with 6 Gy radiation resulting in the largest response. KYSE‑150 cells were primarily killed by inducing paraptosis, which is characterized by extensive cytoplasmic vacuolation. 125I seed radiation induced autophagic flux in both ESCC cell lines, and autophagy inhibition by 3‑methyladenine enhanced radiosensitivity. Furthermore 125I seed radiation induced increased production of reactive oxygen species (ROS) in both ESCC cell lines. Treatment with an ROS scavenger significantly attenuated the effects of 125I seed radiation on endoplasmic reticulum stress, autophagy, apoptosis, paraptotic vacuoles and reduced cell viability. In vivo experiments showed that 125I seed brachytherapy induced ROS generation, initiated cell apoptosis and potential paraptosis, and inhibited cell proliferation and tumor growth. In summary, the results demonstrate that in ESCC cells, 125I seed radiation induces cell death through both apoptosis and paraptosis; and at the same time initiates protective autophagy. Additionally, 125I seed radiation‑induced apoptosis, paraptosis and autophagy was considerably mediated by ROS.

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1	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar
2	Lagergren J, Smyth E, Cunningham D and Lagergren P: Oesophageal cancer. Lancet. 390:2383–2396. 2017. View Article : Google Scholar
3	Jatoi A, Martenson JA, Foster NR, McLeod HL, Lair BS, Nichols F, Tschetter LK, Moore DF Jr, Fitch TR and Alberts SR; North Central Cancer Treatment Group (N0044), : Paclitaxel, carboplatin, 5-fluorouracil, and radiation for locally advanced esophageal cancer: Phase II results of preliminary pharmacologic and molecular efforts to mitigate toxicity and predict outcomes: North central cancer treatment group (N0044). Am J Clin Oncol. 30:507–513. 2007. View Article : Google Scholar
4	Tsushima T, Mizusawa J, Sudo K, Honma Y, Kato K, Igaki H, Tsubosa Y, Shinoda M, Nakamura K, Fukuda H, et al: Risk factors for esophageal fistula associated with chemoradiotherapy for locally advanced unresectable esophageal cancer: A supplementary analysis of JCOG0303. Medicine (Baltimore). 95:e36992016. View Article : Google Scholar :
5	Schnell O, Scholler K, Ruge M, Siefert A, Tonn JC and Kreth FW: Surgical resection plus stereotactic 125I brachytherapy in adult patients with eloquently located supratentorial WHO grade II glioma-feasibility and outcome of a combined local treatment concept. J Neurol. 255:1495–1502. 2008. View Article : Google Scholar
6	Zhang F, Wang J, Guo J, Li Y, Huang X, Guan Z, Lei G, Wang J, Ye X, Zhao X, et al: Chinese expert consensus workshop report: Guideline for permanent iodine-125 seed implantation of primary and metastatic lung tumors. Thorac Cancer. 10:388–394. 2019. View Article : Google Scholar
7	Mo Z, Zhang T, Zhang Y, Xiang Z, Yan H, Zhong Z, Gao F and Zhang F: Feasibility and clinical value of CT-guided (125)I brachytherapy for metastatic soft tissue sarcoma after first-line chemotherapy failure. Eur Radiol. 28:1194–1203. 2018. View Article : Google Scholar
8	Zhuang HQ, Wang JJ, Liao AY, Wang JD and Zhao Y: The biological effect of 125I seed continuous low dose rate irradiation in CL187 cells. J Exp Clin Cancer Res. 28:122009. View Article : Google Scholar :
9	Wang H, Li J, Qu A, Liu J, Zhao Y and Wang J: The different biological effects of single, fractionated and continuous low dose rate irradiation on CL187 colorectal cancer cells. Radiat Oncol. 8:1962013. View Article : Google Scholar :
10	Guo JH, Teng GJ, Zhu GY, He SC, Fang W, Deng G and Li GZ: Self-expandable esophageal stent loaded with 125I seeds: Initial experience in patients with advanced esophageal cancer. Radiology. 247:574–581. 2008. View Article : Google Scholar
11	Zhu HD, Guo JH, Mao AW, Lv WF, Ji JS, Wang WH, Lv B, Yang RM, Wu W, Ni CF, et al: Conventional stents versus stents loaded with (125)iodine seeds for the treatment of unresectable oesophageal cancer: A multicentre, randomised phase 3 trial. Lancet Oncol. 15:612–619. 2014. View Article : Google Scholar
12	Chen HL, Shen WQ and Liu K: Radioactive self-expanding stents for palliative management of unresectable esophageal cancer: A systematic review and meta-analysis. Dis Esophagus. 30:1–16. 2017. View Article : Google Scholar
13	Qu A, Wang H, Li J, Wang J, Liu J, Hou Y, Huang L and Zhao Y: Biological effects of (125)i seeds radiation on A549 lung cancer cells: G2/M arrest and enhanced cell death. Cancer Invest. 32:209–217. 2014. View Article : Google Scholar
14	Wang ZM, Lu J, Zhang LY, Lin XZ, Chen KM, Chen ZJ, Liu FJ, Yan FH, Teng GJ and Mao AW: Biological effects of low-dose-rate irradiation of pancreatic carcinoma cells in vitro using 125I seeds. World J Gastroenterol. 21:2336–2342. 2015. View Article : Google Scholar :
15	Kim BM and Hong Y, Lee S, Liu P, Lim JH, Lee YH, Lee TH, Chang KT and Hong Y: Therapeutic implications for overcoming radiation resistance in cancer therapy. Int J Mol Sci. 16:26880–26913. 2015. View Article : Google Scholar :
16	Hu L, Wang H, Zhao Y and Wang J: (125)I seeds radiation induces paraptosis-like cell death via PI3K/AKT signaling pathway in HCT116 cells. Biomed Res Int. 2016:81454952016. View Article : Google Scholar :
17	Chaurasia M, Bhatt AN, Das A, Dwarakanath BS and Sharma K: Radiation-induced autophagy: Mechanisms and consequences. Free Radic Res. 50:273–290. 2016. View Article : Google Scholar
18	Leidal AM, Levine B and Debnath J: Autophagy and the cell biology of age-related disease. Nat Cell Biol. 20:1338–1348. 2018. View Article : Google Scholar
19	Lu C and Xie C: Radiation-induced autophagy promotes esophageal squamous cell carcinoma cell survival via the LKB1 pathway. Oncol Rep. 35:3559–3565. 2016. View Article : Google Scholar
20	Tao H, Qian P, Lu J, Guo Y, Zhu H and Wang F: Autophagy inhibition enhances radiosensitivity of Eca109 cells via the mitochondrial apoptosis pathway. Int J Oncol. 52:1853–1862. 2018.
21	Lee D, Kim IY, Saha S and Choi KS: Paraptosis in the anti-cancer arsenal of natural products. Pharmacol Ther. 162:120–133. 2016. View Article : Google Scholar
22	Prokhorova EA, Egorshina AY, Zhivotovsky B and Kopeina GS: The DNA-damage response and nuclear events as regulators of nonapoptotic forms of cell death. Oncogene. 39:1–16. 2020. View Article : Google Scholar
23	Chen X, Chen X, Zhang X, Wang L, Cao P, Rajamanickam V, Wu C, Zhou H, Cai Y, Liang G and Wang Y: Curcuminoid B63 induces ROS-mediated paraptosis-like cell death by targeting TrxR1 in gastric cells. Redox Biol. 21:1010612019. View Article : Google Scholar
24	Fontana F, Moretti RM, Raimondi M, Marzagalli M, Beretta G, Procacci P, Sartori P, Montagnani Marelli M and Limonta P: delta-Tocotrienol induces apoptosis, involving endoplasmic reticulum stress and autophagy, and paraptosis in prostate cancer cells. Cell Prolif. 52:e125762019. View Article : Google Scholar :
25	Seo MJ, Lee DM, Kim IY, Lee D, Choi MK, Lee JY, Park SS, Jeong SY, Choi EK and Choi KS: Gambogic acid triggers vacuolization-associated cell death in cancer cells via disruption of thiol proteostasis. Cell Death Dis. 10:1872019. View Article : Google Scholar :
26	Zhao H, Xu X, Lei S, Shao D, Jiang C, Shi J, Zhang Y, Liu L, Lei S, Sun H and Huang Q: Iturin A-like lipopeptides from Bacillus subtilis trigger apoptosis, paraptosis, and autophagy in Caco-2 cells. J Cell Physiol. 234:6414–6427. 2019. View Article : Google Scholar
27	Kessel D: Apoptosis, paraptosis and autophagy: Death and survival pathways associated with photodynamic therapy. Photochem Photobiol. 95:119–125. 2019. View Article : Google Scholar
28	Weinberg F and Chandel NS: Reactive oxygen species-dependent signaling regulates cancer. Cell Mol Life Sci. 66:3663–3673. 2009. View Article : Google Scholar
29	Aird EG, Folkard M, Mayes CR, Bownes PJ, Lawson JM and Joiner MC: A purpose-built iodine-125 irradiation plaque for low dose rate low energy irradiation of cell lines in vitro. Br J Radiol. 74:56–61. 2001. View Article : Google Scholar
30	Gan Z, Jing J, Zhu G, Qin Y, Teng G and Guo J: Preventive effects of (1)(2)(5)I seeds on benign restenosis following esophageal stent implantation in a dog model. Mol Med Rep. 11:3382–3390. 2015. View Article : Google Scholar
31	Fernandez-Capetillo O, Chen HT, Celeste A, Ward I, Romanienko PJ, Morales JC, Naka K, Xia Z, Camerini-Otero RD, Motoyama N, et al: DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1. Nat Cell Biol. 4:993–997. 2002. View Article : Google Scholar
32	Chen YS, Song HX, Lu Y, Li X, Chen T, Zhang Y, Xue JX, Liu H, Kan B, Yang G and Fu T: Autophagy inhibition contributes to radiation sensitization of esophageal squamous carcinoma cells. Dis Esophagus. 24:437–443. 2011. View Article : Google Scholar
33	Shubin AV, Demidyuk IV, Komissarov AA, Rafieva LM and Kostrov SV: Cytoplasmic vacuolization in cell death and survival. Oncotarget. 7:55863–55889. 2016. View Article : Google Scholar :
34	Zaorsky NG, Davis BJ, Nguyen PL, Showalter TN, Hoskin PJ, Yoshioka Y, Morton GC and Horwitz EM: The evolution of brachytherapy for prostate cancer. Nat Rev Urol. 14:415–439. 2017. View Article : Google Scholar
35	Wu C, Li B, Sun G, Peng C and Xiang D: Efficacy and safety of iodine-125 brachytherapy combined with chemotherapy in the treatment of advanced NSCLC in the elderly. Onco Targets Ther. 11:6617–6624. 2018. View Article : Google Scholar :
36	Lehnert S, Reniers B and Verhaegen F: Relative biologic effectiveness in terms of tumor response of 125I implants compared with 60Co gamma rays. Int J Radiat Oncol Biol Phys. 63:224–229. 2005. View Article : Google Scholar
37	Liu C, Wang L, Qiu H, Dong Q, Feng Y, Li D, Li C and Fan C: Combined strategy of radioactive (125)I seeds and salinomycin for enhanced glioma chemo-radiotherapy: Evidences for ROS-mediated apoptosis and signaling crosstalk. Neurochem Res. 43:1317–1327. 2018. View Article : Google Scholar
38	Zhang WF, Jin WD, Li B, Wang MC, Li XG, Mao WY and Luo KY: Effect of brachytherapy on NF-kB and VEGF in gastric carcinoma xenografts. Oncol Rep. 32:635–640. 2014. View Article : Google Scholar
39	Lee DM, Kim IY, Seo MJ, Kwon MR and Choi KS: Nutlin-3 enhances the bortezomib sensitivity of p53-defective cancer cells by inducing paraptosis. Exp Mol Med. 49:e3652017. View Article : Google Scholar :
40	Zhou Y, Huang F, Yang Y, Wang P, Zhang Z, Tang Y, Shen Y and Wang K: Paraptosis-inducing nanomedicine overcomes cancer drug resistance for a potent cancer therapy. Small. 14:2018.
41	Kim JY, Lee DM, Woo HG, Kim KD, Lee HJ, Kwon YJ and Choi KS: RNAi screening-based identification of USP10 as a novel regulator of paraptosis. Sci Rep. 9:49092019. View Article : Google Scholar :
42	Sperandio S, de Belle I and Bredesen DE: An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci USA. 97:14376–14381. 2000. View Article : Google Scholar
43	Wang G, Liu L, Sharma S, Liu H, Yang W, Sun X and Dong Q: Bmi-1 confers adaptive radioresistance to KYSE-150R esophageal carcinoma cells. Biochem Biophys Res Commun. 425:309–314. 2012. View Article : Google Scholar
44	Zhang H, Luo H, Jiang Z, Yue J, Hou Q, Xie R and Wu S: Fractionated irradiation-induced EMT-like phenotype conferred radioresistance in esophageal squamous cell carcinoma. J Radiat Res. 57:370–380. 2016. View Article : Google Scholar :
45	Mirzayans R, Andrais B, Scott A, Wang YW, Kumar P and Murray D: Multinucleated giant cancer cells produced in response to ionizing radiation retain viability and replicate their genome. Int J Mol Sci. 18:E3602017. View Article : Google Scholar
46	Denisenko TV, Sorokina IV, Gogvadze V and Zhivotovsky B: Mitotic catastrophe and cancer drug resistance: A link that must to be broken. Drug Resist Updat. 24:1–12. 2016. View Article : Google Scholar
47	Weihua Z, Lin Q, Ramoth AJ, Fan D and Fidler IJ: Formation of solid tumors by a single multinucleated cancer cell. Cancer. 117:4092–4099. 2011. View Article : Google Scholar :
48	Srinivas US, Tan BWQ, Vellayappan BA and Jeyasekharan AD: ROS and the DNA damage response in cancer. Redox Biol. 25:1010842019. View Article : Google Scholar
49	Zou Z, Chang H, Li H and Wang S: Induction of reactive oxygen species: An emerging approach for cancer therapy. Apoptosis. 22:1321–1335. 2017. View Article : Google Scholar
50	Tang JY, Ou-Yang F, Hou MF, Huang HW, Wang HR, Li KT, Fayyaz S, Shu CW and Chang HW: Oxidative stress-modulating drugs have preferential anticancer effects-involving the regulation of apoptosis, DNA damage, endoplasmic reticulum stress, autophagy, metabolism, and migration. Semin Cancer Biol. 58:109–117. 2019. View Article : Google Scholar