Imperatorin efficiently blocks TNF-α-mediated activation of ROS/PI3K/Akt/NF-κB pathway

Wang,Ke  Si; Lv,Ying; Wang,Zhe; Ma,Juan; Mi,Chunliu; Li,Xuezheng; Xu,Guang  Hua; Piao,Lian  Xun; Zheng,Sheng  Zhe; Jin,Xuejun

doi:10.3892/or.2017.5581

Imperatorin efficiently blocks TNF-α-mediated activation of ROS/PI3K/Akt/NF-κB pathway

Authors:
- Ke Si Wang
- Ying Lv
- Zhe Wang
- Juan Ma
- Chunliu Mi
- Xuezheng Li
- Guang Hua Xu
- Lian Xun Piao
- Sheng Zhe Zheng
- Xuejun Jin
View Affiliations

Affiliations: Key Laboratory of Natural Resources of Changbai Mountain and Functional Molecules, Ministry of Education, Molecular Medicine Research Center, College of Pharmacy, Yanbian University, Yanbian, Jilin 133002, P.R. China, Department of Neurology, Affiliated Hospital of Yanbian University, Yanbian, Jilin 133002, P.R. China
Published online on: April 19, 2017 https://doi.org/10.3892/or.2017.5581
Pages: 3397-3404

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Inflammation contributes to development and progression in a variety of cancers, including cervical cancer, which is the second leading cause of cancer deaths in women worldwide. In this study, we examined the anti-inflammatory effects of imperatorin, a psoralen-type furanocoumarin from the fruits of Angelica dahurica, in tumor necrosis factor-α (TNF-α)-stimulated HeLa cells by investigating its impact on the production and expression of cytokines and the major signal-transduction pathways. We found this compound significantly inhibited the TNF-α-induced expression of NF-κB target genes, such as COX-2, cyclin D1, MMP-9, VEGF, IL-6 and Bcl-xL in a concentration-dependent manner. Further analysis revealed that imperatorin was a potent inhibitor of NF-κB activation by the suppression of TNF-α-induced IKKα/β phosphorylation, IκB phosphorylation and degradation, and NF-κB p65 nuclear translocation. We also demonstrated that imperatorin downregulated TNF-α-induced activation of PI3K/Akt. Furthermore, our findings show that imperatorin inhibits TNF-α-induced ROS generation. Taken together, imperatorin can blunt inflammation by inhibiting the ROS-mediated activation of the PI3K/Akt/NF-κB pathway.

View Figures

View References

1	Lawrence T, Willoughby DA and Gilroy DW: Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat Rev Immunol. 2:787–795. 2002. View Article : Google Scholar : PubMed/NCBI
2	Hayden MS and Ghosh S: NF-κB in immunobiology. Cell Res. 21:223–244. 2011. View Article : Google Scholar : PubMed/NCBI
3	Sethi G, Sung B and Aggarwal BB: TNF: A master switch for inflammation to cancer. Front Biosci. 13:5094–5107. 2008. View Article : Google Scholar : PubMed/NCBI
4	Karin M and Ben-Neriah Y: Phosphorylation meets ubiquitination: The control of NF-[kappa]B activity. Annu Rev Immunol. 18:621–663. 2000. View Article : Google Scholar : PubMed/NCBI
5	Chen J and Chen ZJ: Regulation of NF-κB by ubiquitination. Curr Opin Immunol. 25:4–12. 2013. View Article : Google Scholar : PubMed/NCBI
6	Seo SH and Jeong GS: Fisetin inhibits TNF-α-induced inflammatory action and hydrogen peroxide-induced oxidative damage in human keratinocyte HaCaT cells through PI3K/AKT/Nrf-2-mediated heme oxygenase-1 expression. Int Immunopharmacol. 29:246–253. 2015. View Article : Google Scholar : PubMed/NCBI
7	Bai C, Yang X, Zou K, He H, Wang J, Qin H, Yu X, Liu C, Zheng J, Cheng F, et al: Anti-proliferative effect of RCE-4 from Reineckia carnea on human cervical cancer HeLa cells by inhibiting the PI3K/Akt/mTOR signaling pathway and NF-κB activation. Naunyn Schmiedebergs Arch Pharmacol. 389:573–584. 2016. View Article : Google Scholar : PubMed/NCBI
8	Dickinson BC and Chang CJ: Chemistry and biology of reactive oxygen species in signaling or stress responses. Nat Chem Biol. 7:504–511. 2011. View Article : Google Scholar : PubMed/NCBI
9	Murillo MM, Carmona-Cuenca I, Del Castillo G, Ortiz C, Roncero C, Sánchez A, Fernández M and Fabregat I: Activation of NADPH oxidase by transforming growth factor-beta in hepatocytes mediates up-regulation of epidermal growth factor receptor ligands through a nuclear factor-kappaB-dependent mechanism. Biochem J. 405:251–259. 2007. View Article : Google Scholar : PubMed/NCBI
10	Baek NI, Ahn EM, Kim HY and Park YD: Furanocoumarins from the root of Angelica dahurica. Arch Pharm Res. 23:467–470. 2000. View Article : Google Scholar : PubMed/NCBI
11	Guo W, Sun J, Jiang L, Duan L, Huo M, Chen N, Zhong W, Wassy L, Yang Z and Feng H: Imperatorin attenuates LPS-induced inflammation by suppressing NF-κB and MAPKs activation in RAW 264.7 macrophages. Inflammation. 35:1764–1772. 2012. View Article : Google Scholar : PubMed/NCBI
12	Mi C, Shi H, Ma J, Han LZ, Lee JJ and Jin X: Celastrol induces the apoptosis of breast cancer cells and inhibits their invasion via downregulation of MMP-9. Oncol Rep. 32:2527–2532. 2014.PubMed/NCBI
13	Hwangbo C, Kim J, Lee JJ and Lee JH: Activation of the integrin effector kinase focal adhesion kinase in cancer cells is regulated by crosstalk between protein kinase Calpha and the PDZ adapter protein mda-9/Syntenin. Cancer Res. 70:1645–1655. 2010. View Article : Google Scholar : PubMed/NCBI
14	Jin HR, Jin SZ, Cai XF, Li D, Wu X, Nan JX, Lee JJ and Jin X: Cryptopleurine targets NF-κB pathway, leading to inhibition of gene products associated with cell survival, proliferation, invasion, and angiogenesis. PLoS One. 7:e403552012. View Article : Google Scholar : PubMed/NCBI
15	Aggarwal BB: Nuclear factor-kappaB: The enemy within. Cancer Cell. 6:203–208. 2004. View Article : Google Scholar : PubMed/NCBI
16	Baeuerle PA and Henkel T: Function and activation of NF-kappaB in the immune system. Annu Rev Immunol. 12:141–179. 1994. View Article : Google Scholar : PubMed/NCBI
17	Zhang G and Ghosh S: Toll-like receptor-mediated NF-kappaB activation: A phylogenetically conserved paradigm in innate immunity. J Clin Invest. 107:13–19. 2001. View Article : Google Scholar : PubMed/NCBI
18	Ghosh S and Karin M: Missing pieces in the NF-kappaB puzzle. Cell. 109 Suppl:S81–S96. 2002. View Article : Google Scholar : PubMed/NCBI
19	Kang OH, Lee GH, Choi HJ, Park PS, Chae HS, Jeong SI, Kim YC, Sohn DH, Park H, Lee JH, et al: Ethyl acetate extract from Angelica dahuricae Radix inhibits lipopolysaccharide-induced production of nitric oxide, prostaglandin E2 and tumor necrosis factor-alphavia mitogen-activated protein kinases and nuclear factor-kappaB in macrophages. Pharmacol Res. 55:263–270. 2007. View Article : Google Scholar : PubMed/NCBI
20	Yang PY, Rui YC, Li K, Huang XH, Jiang JM and Yu L: Expression of intercellular adhesion molecule-1 in U937 foam cells and inhibitory effect of imperatorin. Acta Pharmacol Sin. 23:327–330. 2002.PubMed/NCBI
21	Savill J: Apoptosis. Phagocytic docking without shocking. Nature. 392:442–443. 1998. View Article : Google Scholar : PubMed/NCBI
22	Savill J, Dransfield I, Gregory C and Haslett C: A blast from the past: Clearance of apoptotic cells regulates immune responses. Nat Rev Immunol. 2:965–975. 2002. View Article : Google Scholar : PubMed/NCBI
23	Rovere P, Sabbadini MG, Vallinoto C, Fascio U, Recigno M, Crosti M, Ricciardi-Castagnoli P, Balestrieri G, Tincani A and Manfredi AA: Dendritic cell presentation of antigens from apoptotic cells in a proinflammatory context: Role of opsonizing anti-beta2-glycoprotein I antibodies. Arthritis Rheum. 42:1412–1420. 1999. View Article : Google Scholar : PubMed/NCBI
24	Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E and Ben-Neriah Y: NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 431:461–466. 2004. View Article : Google Scholar : PubMed/NCBI
25	Pober JS and Sessa WC: Evolving functions of endothelial cells in inflammation. Nat Rev Immunol. 7:803–815. 2007. View Article : Google Scholar : PubMed/NCBI
26	Hermida N and Balligand JL: Low-density lipoprotein-cholesterol-induced endothelial dysfunction and oxidative stress: The role of statins. Antioxid Redox Signal. 20:1216–1237. 2014. View Article : Google Scholar : PubMed/NCBI
27	Yeom M, Kim JH, Min JH, Hwang MK, Jung HS and Sohn Y: Xanthii fructus inhibits inflammatory responses in LPS-stimulated RAW 264.7 macrophages through suppressing NF-κB and JNK/p38 MAPK. J Ethnopharmacol. 176:394–401. 2015. View Article : Google Scholar : PubMed/NCBI
28	Hoesel B and Schmid JA: The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 12:862013. View Article : Google Scholar : PubMed/NCBI
29	Saito Y, Nishio K, Ogawa Y, Kimata J, Kinumi T, Yoshida Y, Noguchi N and Niki E: Turning point in apoptosis/necrosis induced by hydrogen peroxide. Free Radic Res. 40:619–630. 2006. View Article : Google Scholar : PubMed/NCBI
30	Osaki M, Oshimura M and Ito H: PI3K-Akt pathway: Its functions and alterations in human cancer. Apoptosis. 9:667–676. 2004. View Article : Google Scholar : PubMed/NCBI
31	Porta C and Figlin RA: Phosphatidylinositol-3-kinase/Akt signaling pathway and kidney cancer, and the therapeutic potential of phosphatidylinositol-3-kinase/Akt inhibitors. J Urol. 182:2569–2577. 2009. View Article : Google Scholar : PubMed/NCBI
32	Chen J, Yang H, Wen J, Luo K, Liu Q, Huang Y, Zheng Y, Tan Z, Huang Q and Fu J: NHE9 induces chemoradiotherapy resistance in esophageal squamous cell carcinoma by upregulating the Src/Akt/β-catenin pathway and Bcl-2 expression. Oncotarget. 6:12405–12420. 2015. View Article : Google Scholar : PubMed/NCBI
33	Kim JH, Na HJ, Kim CK, Kim JY, Ha KS, Lee H, Chung HT, Kwon HJ, Kwon YG and Kim YM: The non-provitamin A carotenoid, lutein, inhibits NF-kappaB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-kappaB-inducing kinase pathways: Role of H(2)O(2) in NF-kappaB activation. Free Radic Biol Med. 45:885–896. 2008. View Article : Google Scholar : PubMed/NCBI