Emodin treatment of papillary thyroid cancer cell lines <em>in</em> <em>vitro</em> inhibits proliferation and enhances apoptosis via downregulation of NF‑κB and its upstream TLR4 signaling

Liu,Xin; Wei,Wei; Wu,Yue-Zhang; Wang,Yuan; Zhang,Wei-Wei; Wang,Yong-Ping; Dong,Xiao-Ping; Shi,Qi

doi:10.3892/ol.2023.14101

December-2023 Volume 26 Issue 6

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December-2023 Volume 26 Issue 6

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Article Open Access

Emodin treatment of papillary thyroid cancer cell lines in vitro inhibits proliferation and enhances apoptosis via downregulation of NF‑κB and its upstream TLR4 signaling

Authors:
- Xin Liu
- Wei Wei
- Yue-Zhang Wu
- Yuan Wang
- Wei-Wei Zhang
- Yong-Ping Wang
- Xiao-Ping Dong
- Qi Shi
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Affiliations: Basic Medical College, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou 550025, P.R. China, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Head and Neck Surgery, Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China, National Key‑Laboratory of Intelligent Tracing and Forecasting for Infectious Disease, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, P.R. China

Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Article Number: 514
|
Published online on: October 13, 2023

https://doi.org/10.3892/ol.2023.14101
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Abstract

Thyroid cancer is one of the most common types of endocrine malignancy. In addition to surgical treatment, it is very important to find new treatment methods. The aim of the present study was to evaluate the effect of 1,3,8‑trihydroxy‑6‑methylanthraquinone (emodin) on cellular NF‑κB components and the upstream regulatory pathway of toll‑like receptor 4 (TLR4) signaling, as well as the invasion and migration of papillary thyroid carcinoma (PTC) cells. The protein expression of NF‑κB components p65 and p50 and their phosphorylated (p‑) forms in the sections of PTC tissues was measured by individual immunohistochemical assays. PTC cell lines TPC‑1 and IHH4 were exposed to 20 and 40 µM emodin for 24 h. The levels of the NF‑κB components p65, p50, c‑Rel, p‑p65 and p‑p50, elements in TLR4 signaling, including TLR4, MYD88 innate immune signal transduction adaptor (MyD88), interferon regulatory factor 3, AKT and MEK, and proliferative and apoptotic biomarkers, including c‑Myc, cyclin D1, proliferating cell nuclear antigen, Bcl‑2 and Bax, were evaluated by western blotting and immunofluorescent assays. The invasion and migration of PTC cell lines exposed to emodin were tested by plate colony and wound healing assay. Compared with hyperplasia tissue, the expression levels of NF‑κB components p65 and p50, and p‑p65 and p‑p50 in PTC tissue were significantly increased. Treatment of PTC cell lines with emodin lead to significantly reduced levels of the aforementioned NF‑κB components, accompanied by markedly downregulated TLR4 signaling. MYD 88‑dependent and ‑independent pathways, are also significantly down‑regulated. Downregulation of proliferative factors and activation of apoptotic factors were observed in the cell lines following treatment with emodin. Consequently, inhibition of the invasion and migration activities were observed in the emodin‑treated PTC cells. Emodin could inhibit proliferation and promote apoptosis of PTC cells, which is dependent on the downregulation of cellular NF‑κB and the TLR4 signaling pathway.

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1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2019. CA Cancer J Clin. 69:7–34. 2019. View Article : Google Scholar : PubMed/NCBI
2	Lloyd RV, Osamura RY, Klöppel G and Rosai J: WHO classification of tumours of endocrine organs. 4th edition. IARC Publications; Lyon: 2017
3	Saini S, Tulla K, Maker AV, Burman KD and Prabhakar BS: Therapeutic advances in anaplastic thyroid cancer: A current perspective. Mol Cancer. 17:1542018. View Article : Google Scholar : PubMed/NCBI
4	Fagin JA and Wells SA Jr: Biologic and clinical perspectives on thyroid cancer. N Engl J Med. 375:1054–1067. 2016. View Article : Google Scholar : PubMed/NCBI
5	Boumahdi S and de Sauvage FJ: The great escape: Tumour cell plasticity in resistance to targeted therapy. Nat Rev Drug Discov. 19:39–56. 2020. View Article : Google Scholar : PubMed/NCBI
6	Zeng P, Shi Y, Wang XM, Lin L, Du YJ, Tang N, Wang Q, Fang YY, Wang JZ, Zhou XW, et al: Emodin rescued hyperhomocysteinemia-induced dementia and Alzheimer's disease-like features in rats. Int J Neuropsychopharmacol. 22:57–70. 2019. View Article : Google Scholar : PubMed/NCBI
7	Wang X, Wang J, Shi X, Pan C, Liu H, Dong Y, Dong R, Mang J and Xu Z: Proteomic analyses identify a potential mechanism by which extracellular vesicles aggravate ischemic stroke. Life Sci. 231:1165272019. View Article : Google Scholar : PubMed/NCBI
8	Fu JM, Zhou J, Shi J, Xie JS, Huang L, Yip AY, Loo WT, Chow LW and Ng EL: Emodin affects ERCC1 expression in breast cancer cells. J Transl Med. 10 (Suppl 1):S72012. View Article : Google Scholar : PubMed/NCBI
9	Wang Y, Yu H, Zhang J, Ge X, Gao J, Zhang Y and Lou G: Anti-tumor effect of emodin on gynecological cancer cells. Cell Oncol (Dordr). 38:353–363. 2015. View Article : Google Scholar : PubMed/NCBI
10	Zhou RS, Wang XW, Sun QF, Ye ZJ, Liu JW, Zhou DH and Tang Y: Anticancer effects of emodin on HepG2 cell: Evidence from bioinformatic analysis. Biomed Res Int. 2019:30658182019. View Article : Google Scholar : PubMed/NCBI
11	Yang Q, Leong SA, Chan KP, Yuan XL and Ng TK: Complex effect of continuous curcumin exposure on human bone marrow-derived mesenchymal stem cell regenerative properties through matrix metalloproteinase regulation. Basic Clin Pharmacol Toxicol. 128:141–153. 2021. View Article : Google Scholar : PubMed/NCBI
12	Stompor-Gorący M: The health benefits of emodin, a natural anthraquinone derived from rhubarb-a summary update. Int J Mol Sci. 22:95222021. View Article : Google Scholar : PubMed/NCBI
13	Zhang Q, Chen WW, Sun X, Qian D, Tang DD, Zhang LL, Li MY, Wang LY, Wu CJ and Peng W: The versatile emodin: A natural easily acquired anthraquinone possesses promising anticancer properties against a variety of cancers. Int J Biol Sci. 18:3498–3527. 2022. View Article : Google Scholar : PubMed/NCBI
14	Chen F, Li M and Zhu X: Propofol suppresses proliferation and migration of papillary thyroid cancer cells by down-regulation of lncRNA ANRIL. Exp Mol Pathol. 107:68–76. 2019. View Article : Google Scholar : PubMed/NCBI
15	Le F, Luo P, Ouyang Q and Zhong X: LncRNA WT1-AS downregulates survivin by upregulating miR-203 in papillary thyroid carcinoma. Cancer Manag Res. 12:443–449. 2020. View Article : Google Scholar : PubMed/NCBI
16	Wang N, Duan H, Zhang C, Zhou Y and Gao R: The LINC01186 suppresses cell proliferation and invasion ability in papillary thyroid carcinoma. Oncol Lett. 16:5639–5644. 2018.PubMed/NCBI
17	Qiu XX, Sun J, Zhao M, Chu X, An J and Li W: Inhibitory effects of emodin on the biological activity of human papillary thyroid cancer cells and related mechanisms. Acta Acad Med Xuzhou. 41:367–372. 2021.(In Chinese).
18	Rajendran V and Jain MV: In vitro tumorigenic assay: Colony forming assay for cancer stem cells. Methods Mol Biol. 1692:89–95. 2018. View Article : Google Scholar : PubMed/NCBI
19	Pramanik KC, Makena MR, Bhowmick K and Pandey MK: Advancement of NF-κB signaling pathway: A novel target in pancreatic cancer. Int J Mol Sci. 19:38902018. View Article : Google Scholar : PubMed/NCBI
20	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
21	Li W, Wang D, Li M and Li B: Emodin inhibits the proliferation of papillary thyroid carcinoma by activating AMPK. Exp Ther Med. 22:10752021. View Article : Google Scholar : PubMed/NCBI
22	Zhang W, Peng Y and Teng Y: Inhibitory effects of emodin alone and its combination with gemcitabine on human thyroid cancer cell K1. Chin J Tradit Med Sci Technol. 28:733–738. 2021.(In Chinese).
23	Shi GH and Zhou L: Emodin suppresses angiogenesis and metastasis in anaplastic thyroid cancer by affecting TRAF6-mediated pathways in vivo and in vitro. Mol Med Rep. 18:5191–5197. 2018.PubMed/NCBI
24	Yamamoto Y and Gaynor RB: Role of the NF-kB pathway in the pathogenesis of human disease states. Curr Mol Med. 1:287–296. 2001. View Article : Google Scholar : PubMed/NCBI
25	Zinatizadeh MR, Schock B, Chalbatani GM, Zarandi PK, Jalali SA and Miri SR: The nuclear factor kappa B (NF-kB) signaling in cancer development and immune diseases. Genes Dis. 8:287–297. 2020. View Article : Google Scholar : PubMed/NCBI
26	Ledoux AC and Perkins ND: NF-κB and the cell cycle. Biochem Soc Trans. 42:76–81. 2014. View Article : Google Scholar : PubMed/NCBI
27	Bacher S and Schmitz ML: The NF-kappaB pathway as a potential target for autoimmune disease therapy. Curr Pharm Des. 10:2827–2837. 2004. View Article : Google Scholar : PubMed/NCBI
28	Geng Xue CW and Lin Xiaoyue: Mechanism of NF-κB signaling pathway regulating lung cancer and research progress in intervention of traditional Chinese medicine. Chin J Exp Tradit Med Formulae. 1–11. 2023.
29	Sun J X, Yy and Li JH: Expression&clinical significance of NF-κB in papillary thyroid carcinoma(PTC). J Microbiol. 35:58–61. 2015.
30	Faria M, Matos P, Pereira T, Cabrera R, Cardoso BA, Bugalho MJ and Silva AL: RAC1b overexpression stimulates proliferation and NF-kB-mediated anti-apoptotic signaling in thyroid cancer cells. PLoS One. 12:e01726892017. View Article : Google Scholar : PubMed/NCBI
31	Liu Y, Li T, Xu Y, Xu E, Zhou M, Wang B and Shen J: Effects of TLR4 gene silencing on the proliferation and apotosis of hepatocarcinoma HEPG2 cells. Oncol Lett. 11:3054–3060. 2016. View Article : Google Scholar : PubMed/NCBI
32	Zhang H and Zhang S: The expression of Foxp3 and TLR4 in cervical cancer: Association with immune escape and clinical pathology. Arch Gynecol Obstet. 295:705–712. 2017. View Article : Google Scholar : PubMed/NCBI
33	Roy A, Srivastava M, Saqib U, Liu D, Faisal SM, Sugathan S, Bishnoi S and Baig MS: Potential therapeutic targets for inflammation in toll-like receptor 4 (TLR4)-mediated signaling pathways. Int Immunopharmacol. 40:79–89. 2016. View Article : Google Scholar : PubMed/NCBI
34	Zhou J, Deng Y, Li F, Yin C, Shi J and Gong Q: Icariside II attenuates lipopolysaccharide-induced neuroinflammation through inhibiting TLR4/MyD88/NF-κB pathway in rats. Biomed Pharmacother. 111:315–324. 2019. View Article : Google Scholar : PubMed/NCBI
35	Yin H, Pu N, Chen Q, Zhang J, Zhao G, Xu X, Wang D, Kuang T, Jin D, Lou W and Wu W: Gut-derived lipopolysaccharide remodels tumoral microenvironment and synergizes with PD-L1 checkpoint blockade via TLR4/MyD88/AKT/NF-κB pathway in pancreatic cancer. Cell Death Dis. 12:10332021. View Article : Google Scholar : PubMed/NCBI
36	Mitra A, Ahuja A, Rahmawati L, Kim HG, Woo BY, Hong YD, Hossain MA, Zhang Z, Kim SY, Lee J, et al: Caragana rosea Turcz methanol extract inhibits lipopolysaccharide-induced inflammatory responses by suppressing the TLR4/NF-κB/IRF3 signaling pathways. Molecules. 26:66602021. View Article : Google Scholar : PubMed/NCBI
37	Chen X, Zhi X, Yin Z, Li X, Qin L, Qiu Z and Su J: 18β-Glycyrrhetinic acid inhibits osteoclastogenesis in vivo and in vitro by blocking RANKL-mediated RANK-TRAF6 interactions and NF-κB and MAPK signaling pathways. Front Pharmacol. 9:6472018. View Article : Google Scholar : PubMed/NCBI
38	Li T, Li X, Zamani A, Wang W, Lee CN, Li M, Luo G, Eiler E, Sun H, Ghosh S, et al: c-Rel is a myeloid checkpoint for cancer immunotherapy. Nat Cancer. 1:507–517. 2020. View Article : Google Scholar : PubMed/NCBI
39	Hunter JE, Leslie J and Perkins ND: c-Rel and its many roles in cancer: An old story with new twists. Br J Cancer. 114:1–6. 2016. View Article : Google Scholar : PubMed/NCBI
40	Wang S, Liu Z, Wang L and Zhang X: NF-kappaB signaling pathway, inflammation and colorectal cancer. Cell Mol Immunol. 6:327–334. 2009. View Article : Google Scholar : PubMed/NCBI
41	Xia Y, Shen S and Verma IM: NF-κB, an active player in human cancers. Cancer Immunol Res. 2:823–830. 2014. View Article : Google Scholar : PubMed/NCBI
42	Taniguchi K and Karin M: NF-κB, inflammation, immunity and cancer: Coming of age. Nat Rev Immunol. 18:309–324. 2018. View Article : Google Scholar : PubMed/NCBI
43	Yan W, XU F, Liu A, Cai J and Wang S: Effect of Toll like-receptor 4 on proliferation of cervical cancer cells by NF-κB signaling pathway. Chin J Pathophysiol. 301–307. 2015.
44	Limaiem F, Rehman A, Anastasopoulou C and Mazzoni T: Papillary thyroid carcinoma. StatPearls [Internet] Treasure Island (FL): StatPearls Publishing; 2023
45	National Health Commission of the People's Republic of China Medical Administration and Medical Administration, . Thyroid Cancer Diagnosis and Treatment Guidelines (2022 Edition). Chin J Pract Surg. 42:1343–1357+1363. 2022.(In Chinese).