Epoxymicheliolide, a novelguaiane-type sesquiterpene lactone, inhibits NF‑κB/COX‑2 signaling pathways by targeting leucine 281 and leucine 25 in IKKβ in renal cell carcinoma

Zhu,Jiabin; Zhao,Jun; Yu,Zhenlong; Shrestha,Sandeep; Song,Jing; Liu,Wenwen; Lan,Wen; Xing,Jinshan; Liu,Shuang; Chen,Chen; Cao,Momo; Sun,Xiuzhen; Wang,Qi; Song,Xishuang

doi:10.3892/ijo.2018.4460

Epoxymicheliolide, a novelguaiane-type sesquiterpene lactone, inhibits NF‑κB/COX‑2 signaling pathways by targeting leucine 281 and leucine 25 in IKKβ in renal cell carcinoma

Authors:
- Jiabin Zhu
- Jun Zhao
- Zhenlong Yu
- Sandeep Shrestha
- Jing Song
- Wenwen Liu
- Wen Lan
- Jinshan Xing
- Shuang Liu
- Chen Chen
- Momo Cao
- Xiuzhen Sun
- Qi Wang
- Xishuang Song
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Affiliations: Department of Urology, The First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, P.R. China, Department of Neurosurgery, The First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, P.R. China, College of Pharmacy, Dalian Medical University, Dalian, Liaoning 116044, P.R. China, Department of Respiratory Medicine, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116023, P.R. China, Department of Neurosurgery, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116023, P.R. China, Department of Gastroenterology, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116023, P.R. China, Department of Cardiovascular Medicine, The First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, P.R. China, Department of Hepatobiliary Surgery, The First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116011, P.R. China, Department of Otorhinolaryngology, The Second Affiliated Hospital, Dalian Medical University, Dalian, Liaoning 116023, P.R. China
Published online on: June 29, 2018 https://doi.org/10.3892/ijo.2018.4460
Pages: 987-1000
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Parthenolide (PTL) is a sesquiterpene lactone compound obtained from Tanacetum parthenium (feverfew) and inhibits the activation of nuclear factor (NF)-κB. Epoxymicheliolide (EMCL) is a compound which is structurally related to PTL; however, EMCL is more stable under acidic and alkaline conditions. As a biologically active molecule, the detailed mechanism by which EMCL inhibits tumor activity remains to be elucidated. The present study evaluated the effect of EMCL on renal cell carcinoma (RCC) cells and identified the underlying mechanisms. It was found that treatment with EMCL significantly inhibited the proliferation of RCC cells in vitro and increased the induction of apoptosis by activating the mitochondria- and caspase-dependent pathway. Simultaneously, EMCL suppressed cell invasion and metastasis by inhibiting epithelial-mesenchymal transition, as observed in a microfluidic chip assay. Furthermore, using immunoﬂuorescence analysis, an electrophoretic mobility shift assay and a dual-luciferase reporter assay, it was shown that treatment with EMCL significantly suppressed the expression of cyclooxygenase‑2 by inhibiting the translocation of NF‑κB p50/p65 and the activity of NF‑κB. Collectively, the results indicated that EMCL suppressed tumor growth by inhibiting the activation of NF‑κB and suggested that EMCL may be a novel anticancer agent in the treatment of RCC.

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1	Zhou S, Wang J and Zhang Z: An emerging understanding of long noncoding RNAs in kidney cancer. J Cancer Res Clin Oncol. 140:1989–1995. 2014. View Article : Google Scholar : PubMed/NCBI
2	Smaletz O: Current management and future directions in the treatment of advanced renal cell carcinoma - a latin american perspective: 10 years in review. Int Braz J Urol. 41:835–843. 2015. View Article : Google Scholar : PubMed/NCBI
3	Lu J, Wei JH, Feng ZH, Chen ZH, Wang YQ, Huang Y, Fang Y, Liang YP, Cen JJ, Pan YH, et al: miR-106b-5p promotes renal cell carcinoma aggressiveness and stem-cell-like phenotype by activating Wnt/β-catenin signalling. Oncotarget. 8:21461–21471. 2017.PubMed/NCBI
4	Heinrich M, Robles M, West JE, Ortiz de Montellano BR and Rodriguez E: Ethnopharmacology of Mexican asteraceae (Compositae). Annu Rev Pharmacol Toxicol. 38:539–565. 1998. View Article : Google Scholar : PubMed/NCBI
5	Liao K, Xia B, Zhuang QY, Hou MJ, Zhang YJ, Luo B, Qiu Y, Gao YF, Li XJ, Chen HF, et al: Parthenolide inhibits cancer stem-like side population of nasopharyngeal carcinoma cells via suppression of the NF-κB/COX-2 pathway. Theranostics. 5:302–321. 2015. View Article : Google Scholar :
6	Saadane A, Masters S, DiDonato J, Li J and Berger M: Parthenolide inhibits IkappaB kinase, NF-kappaB activation, and inflammatory response in cystic fibrosis cells and mice. Am J Respir Cell Mol Biol. 36:728–736. 2007. View Article : Google Scholar : PubMed/NCBI
7	Oka D, Nishimura K, Shiba M, Nakai Y, Arai Y, Nakayama M, Takayama H, Inoue H, Okuyama A and Nonomura N: Sesquiterpene lactone parthenolide suppresses tumor growth in a xenograft model of renal cell carcinoma by inhibiting the activation of NF-kappaB. Int J Cancer. 120:2576–2581. 2007. View Article : Google Scholar : PubMed/NCBI
8	Lin M, Bi H, Yan Y, Huang W, Zhang G, Zhang G, Tang S, Liu Y, Zhang L, Ma J, et al: Parthenolide suppresses non-small cell lung cancer GLC-82 cells growth via B-Raf/MAPK/Erk pathway. Oncotarget. 8:23436–23447. 2017.PubMed/NCBI
9	Kim SL, Kim SH, Park YR, Liu YC, Kim EM, Jeong HJ, Kim YN, Seo SY, Kim IH, Lee SO, et al: Combined parthenolide and balsalazide have enhanced antitumor efficacy through blockade of NF-κB activation. Mol Cancer Res. 15:141–151. 2017. View Article : Google Scholar : PubMed/NCBI
10	Liu W, Wang X, Sun J, Yang Y, Li W and Song J: Parthenolide suppresses pancreatic cell growth by autophagy-mediated apoptosis. OncoTargets Ther. 10:453–461. 2017. View Article : Google Scholar
11	Pei S, Minhajuddin M, D'Alessandro A, Nemkov T, Stevens BM, Adane B, Khan N, Hagen FK, Yadav VK, De S, et al: Rational design of a parthenolide-based drug regimen that selectively eradicates acute myelogenous leukemia stem cells. J Biol Chem. 291:21984–22000. 2016. View Article : Google Scholar : PubMed/NCBI
12	Jeyamohan S, Moorthy RK, Kannan MK and Arockiam AJ: Parthenolide induces apoptosis and autophagy through the suppression of PI3K/Akt signaling pathway in cervical cancer. Biotechnol Lett. 38:1251–1260. 2016. View Article : Google Scholar : PubMed/NCBI
13	Jin P, Madieh S and Augsburger LL: The solution and solid state stability and excipient compatibility of parthenolide in feverfew. AAPS PharmSciTech. 8:E1052007. View Article : Google Scholar
14	Yu Z, Guo W, Ma X, Zhang B, Dong P, Huang L, Wang X, Wang C, Huo X, Yu W, et al: Gamabufotalin, a bufadienolide compound from toad venom, suppresses COX-2 expression through targeting IKKβ/NF-κB signaling pathway in lung cancer cells. Mol Cancer. 13:2032014. View Article : Google Scholar
15	Karin M: Nuclear factor-kappaB in cancer development and progression. Nature. 441:431–436. 2006. View Article : Google Scholar : PubMed/NCBI
16	Mantovani A, Allavena P, Sica A and Balkwill F: Cancer-related inflammation. Nature. 454:436–444. 2008. View Article : Google Scholar : PubMed/NCBI
17	Kankaya D, Kiremitci S, Tulunay O and Baltaci S: Gelsolin, NF-κB, and p53 expression in clear cell renal cell carcinoma: Impact on outcome. Pathol Res Pract. 211:505–512. 2015. View Article : Google Scholar : PubMed/NCBI
18	Peri S, Devarajan K, Yang DH, Knudson AG and Balachandran S: Meta-analysis identifies NF-κB as a therapeutic target in renal cancer. PLoS One. 8:e767462013. View Article : Google Scholar
19	Ohshima H, Tazawa H, Sylla BS and Sawa T: Prevention of human cancer by modulation of chronic inflammatory processes. Mutat Res. 591:110–122. 2005. View Article : Google Scholar : PubMed/NCBI
20	Surh YJ, Chun KS, Cha HH, Han SS, Keum YS, Park KK and Lee SS: Molecular mechanisms underlying chemopreventive activities of anti-inflammatory phytochemicals: Down-regulation of COX-2 and iNOS through suppression of NF-kappa B activation. Mutat Res. 480–481:243–268. 2001. View Article : Google Scholar
21	Dannenberg AJ, Altorki NK, Boyle JO, Dang C, Howe LR, Weksler BB and Subbaramaiah K: Cyclo-oxygenase 2: A pharmacological target for the prevention of cancer. Lancet Oncol. 2:544–551. 2001. View Article : Google Scholar
22	Williams CS, Mann M and DuBois RN: The role of cyclooxygenases in inflammation, cancer, and development. Oncogene. 18:7908–7916. 1999. View Article : Google Scholar
23	Erdem H, Aydin HR, Bahadir A, Gündogdu B, Balta H, Sener E, Kayikci MA, Albayrak A and Erdogan F: Relationship of CD95 and COX-2 in renal cell carcinomas with survival and other prognostic parameters: A tissue microarray study. J Pak Med Assoc. 65:597–601. 2015.PubMed/NCBI
24	Yang S, Gao Q and Jiang W: Relationship between tumour angiogenesis and expression of cyclo-oxygenase-2 and vascular endothelial growth factor-A in human renal cell carcinoma. J Int Med Res. 43:110–117. 2015. View Article : Google Scholar
25	Shrestha S, Zhu J, Wang Q, Du X, Liu F, Jiang J, Song J, Xing J, Sun D, Hou Q, et al: Melatonin potentiates the antitumor effect of curcumin by inhibiting IKKβ/NF-κB/COX-2 signaling pathway. Int J Oncol. 51:1249–1260. 2017. View Article : Google Scholar : PubMed/NCBI
26	Zhao H, Wang J, Kong X, Li E, Liu Y, Du X, Kang Z, Tang Y, Kuang Y, Yang Z, et al: CD47 promotes tumor invasion and metastasis in non-small cell lung cancer. Sci Rep. 6:297192016. View Article : Google Scholar : PubMed/NCBI
27	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
28	Hu Q, Hou YC, Huang J, Fang JY and Xiong H: Itraconazole induces apoptosis and cell cycle arrest via inhibiting Hedgehog signaling in gastric cancer cells. J Exp Clin Cancer Res. 36:502017. View Article : Google Scholar : PubMed/NCBI
29	Wang X, Yu Z, Wang C, Cheng W, Tian X, Huo X, Wang Y, Sun C, Feng L, Xing J, et al: Alantolactone, a natural sesquiterpene lactone, has potent antitumor activity against glioblastoma by targeting IKKβ kinase activity and interrupting NF-κB/COX-2-mediated signaling cascades. J Exp Clin Cancer Res. 36:932017. View Article : Google Scholar
30	Zhang C, Su ZY, Wang L, Shu L, Yang Y, Guo Y, Pung D, Bountra C and Kong AN: Epigenetic blockade of neoplastic transformation by bromodomain and extra-terminal (BET) domain protein inhibitor JQ-1. Biochem Pharmacol. 117:35–45. 2016. View Article : Google Scholar : PubMed/NCBI
31	Knight DW: Feverfew: Chemistry and biological activity. Nat Prod Rep. 12:271–276. 1995. View Article : Google Scholar : PubMed/NCBI
32	Boolbol SK, Dannenberg AJ, Chadburn A, Martucci C, Guo XJ, Ramonetti JT, Abreu-Goris M, Newmark HL, Lipkin ML, DeCosse JJ, et al: Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res. 56:2556–2560. 1996.PubMed/NCBI
33	Zimmermann KC, Sarbia M, Weber AA, Borchard F, Gabbert HE and Schrör K: Cyclooxygenase-2 expression in human esophageal carcinoma. Cancer Res. 59:198–204. 1999.PubMed/NCBI
34	Heiss E, Herhaus C, Klimo K, Bartsch H and Gerhäuser C: Nuclear factor kappa B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms. J Biol Chem. 276:32008–32015. 2001. View Article : Google Scholar : PubMed/NCBI
35	Lee DF and Hung MC: Advances in targeting IKK and IKK-related kinases for cancer therapy. Clin Cancer Res. 14:5656–5662. 2008. View Article : Google Scholar : PubMed/NCBI
36	Horejs CM: Basement membrane fragments in the context of the epithelial-to-mesenchymal transition. Eur J Cell Biol. 95:427–440. 2016. View Article : Google Scholar : PubMed/NCBI
37	Gomez DE, Alonso DF, Yoshiji H and Thorgeirsson UP: Tissue inhibitors of metalloproteinases: Structure, regulation and biological functions. Eur J Cell Biol. 74:111–122. 1997.PubMed/NCBI