Nobiletin inhibits breast cancer via p38 mitogen-activated protein kinase, nuclear transcription factor-κB, and nuclear factor erythroid 2-related factor 2 pathways in MCF-7 cells
Introduction: Breast cancer is one of the most commonly diagnosed cancers in women, with a high mortality rate.
Objective: In the present study, we evaluated the anticancer effect of nobiletin, a flavone glycoside, on the breast cancer cell line MCF-7.
Result: Cell viability and proliferation decreased and cell morphology changed from diamond to round after being treated with nobiletin. Nobiletin induced apoptosis of breast cancer MCF-7 cells via regulating the protein expression of Bax, Bcl-2, cleaved caspase-3, and p53. The expression of Bcl-2 decreased, while the expression of Bax and p53 increased in MCF-7 cells treated with nobiletin. Meanwhile, nobiletin inhibited cell migration by downregulating the protein expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). Moreover, phosphorylation of p38 was increased, and the translocation of p65 and nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus was decreased, which suggested that the anticancer effects of nobiletin might at least partially rely on mediating the p38 mitogen-activated protein kinase, nuclear transcription factor-κB, and Nrf2 pathways in MCF-7 breast cancer cells.
Conclusion and recommendation: Our data showed that nobiletin was a potential antitumor drug, and it provided some experimental basis for the clinical application of tumor therapy.
- DeSantis CE, Siegel RL, Sauer AG, Miller KD, Fedewa SA, Jemal A, et al. Cancer statistics for African Americans, 2016: progress and opportunities in reducing racial disparities. Ca-Cancer J Clin 2016; 66: 290–308. doi: 10.3322/caac.21340.a
- Abou-El-Naga A, Shaban A, Ghazy H, Elsaid A, Elshazli R, Settin A, et al. Frequency of BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) mutations in Egyptian women with breast cancer compared to healthy controls. Meta Gene 2018; 15: 35–41. doi: 10.1016/j.mgene.2017.11.002.
- Dunning AM, Healey CS, Pharoah PD, Teare MD, Ponder BA. A systematic review of genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 1999; 8: 843–54.
- Ahmedin J, Rebecca S, Elizabeth W, Taylor M, Xu J, Michael J, et al. Cancer Statistics, 2006. Ca-Cancer J Clin 2006; 56: 106–30. doi: 10.3322/canjclin.56.2.106.
- Aztopal N, Erkisa M, Erturk E, Ulukaya E, Tokullugil AH, Ari F. Valproic acid, a histone deacetylase inhibitor, induces apoptosis in breast cancer stem cells. Chem Biol Interact 2017; 280: 51–8. doi: 10.1016/j.cbi.2017.12.003.
- Zhao Y, Jing Z, Lv J, Zhang Z, Lin J, Zhao Z, et al. Berberine activates caspase-9/cytochrome c-mediated apoptosis to suppress triple-negative breast cancer cells in vitro and in vivo. Biomed Pharmacother 2017; 95: 18–24. doi: 10.1016/j.biopha.2017.08.045.
- Song W, Yan CY, Zhou QQ, Zhen LL. Galangin potentiates human breast cancer to apoptosis induced by TRAIL through activating AMPK. Biomed Pharmacother 2017; 89: 845–56. doi: 10.1016/j.biopha.2017.01.062.
- Yang JS, Yang SF. Nobiletin inhibits human osteosarcoma cells metastasis by NF-κB-, and CREB-dependent down-regulation of MMPs via ERK and JNK pathway. Eur J Cancer 2016; 61: S51. doi: 10.1016/S0959-8049(16)61170-X.
- Miyata Y, Sato T, Imada K, Dobashi A, Yano M, Ito A. A citrus polymethoxyflavonoid, nobiletin, is a novel MEK inhibitor that exhibits antitumor metastasis in human fibrosarcoma HT-1080 cells. Biochem Biophys Res Commun 2008; 366: 168–73. doi:org/10.1016/j.bbrc.2007.11.100.
- Lee AC, Hsiao WC, Wright DE, Chong SY, Leow SK, Kao CF, et al. Induction of GADD45α expression contributes to the anti-proliferative effects of polymethoxyflavones on colorectal cancer cells. J Funct Foods 2013; 5: 616–24. doi: 10.1016/j.jff.2013.01.003.
- Shi MD, Liao YC, Shih YW, Tsai LY. Nobiletin attenuates metastasis via both ERK and PI3K/Akt pathways in HGF-treated liver cancer HepG2 cells. Phytomedicine 2013; 20: 743–52. doi: 10.1016/j.phymed.2013.02.004.
- Surichan S, Androutsopoulos VP, Sifakis S, Koutala E, Tsatsakis A, Boarder MR, et al. Bioactivation of the citrus flavonoid nobiletin by CYP1 enzymes in MCF7 breast adenocarcinoma cells. Food Chem Toxicol 2012; 50: 3320–8. doi: 10.1016/j.fct.2012.06.030.
- Cao J, Tong C, Liu Y, Wang J, Ni X, Xiong MM, et al. Ginkgetin inhibits growth of breast carcinoma via regulating MAPKs pathway. Biomed Pharmacother 2017; 96: 450–8. doi: 10.1016/j.biopha.2017.09.077.
- Bodur C, Kutuk O, Karsli-Uzunbas G, Isimjan TT, Harrison P, Basaga H, et al. Pramanicin analog induces apoptosis in human colon cancer cells: critical roles for Bcl-2, Bim, and p38 MAPK signaling. PLoS One 2013; 8: e56369. doi: 10.1371/journal.pone.0056369.
- Azijli K, Yuvaraj S, Flach K, Giovannetti E, Peters GJ, Jong SD, et al. MAPK p38 and JNK have opposing activities on TRAIL-induced apoptosis activation in NSCLC H460 cells that involves RIP1 and caspase-8 and is mediated by Mcl-1. Apoptosis 2013; 18: 851–60. doi: 10.1007/s10495-013-0829-3.
- Tan N, Wong M, Nannini MA, Hong R, Lee LB, Belmont LD, et al. Bcl-2/Bcl-xL inhibition increases the efficacy of MEK inhibition alone and in combination with PI3 kinase inhibition in lung and pancreatic tumor models. Mol Cancer Ther 2013; 12: 853–64. doi: 10.1158/1535-7163.MCT-12-0949.
- Maier HJ, Schmidt-Strassburger U, Huber MA, Wiedemann EM, Beug H, Wirth T. NF-kappaB promotes epithelial-mesenchymal transition, migration and invasion of pancreatic carcinoma cells. Cancer Lett 2010; 295: 214–228. doi: 10.1016/j.canlet.2010.03.003.
- Bharti AC, Aggarwal BB. Nuclear factor-kappa B and cancer: its role in prevention and therapy. Biochem Pharmacol 2002; 64: 883–8. doi: 10.1016/S0006-2952(02)01154-1.
- Yuan Z, Jiang H, Zhu X, Liu X, Li J. Ginsenoside Rg3 promotes cytotoxicity of Paclitaxel through inhibiting NF-κB signaling and regulating Bax/Bcl-2 expression on triple-negative breast cancer. Biomed Pharmacother 2017; 89: 227–32. doi: 10.1016/j.biopha.2017.02.038.
- Perkins ND. The diverse and complex roles of NF-κB subunits in cancer. Nat Rev Cancer 2012; 12: 121–132. doi: 10.1038/nrc3204.
- Cho HY, Reddy SP, Kleeberger SR. Nrf2 defends the lung from oxidative stress. Antioxid Redox Signal 2006; 8: 76–87. doi: 10.1089/ars.2006.8.76.
- Tang X, Wang H, Fan L, Wu X, Xin A, Ren H, et al. Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs. Free Radic Biol Med 2011; 50: 1599–609. doi: 10.1016/j.freeradbiomed.2011.03.008.
- Lei JC, Yu JQ, Yin Y, Liu YW, Zou GL. Alantolactone induces activation of apoptosis in human hepatoma cells. Food Chem Toxicol 2012; 50: 3313–19. doi: 10.1016/j.fct.2012.06.014.
- Feng C, Xian Q, Liu S. Micro RNA-518 inhibits gastric cancer cell growth by inducing apoptosis via targeting MDM2. Biomed Pharmacother 2018; 97: 1595–602. doi: 10.1016/j.biopha.2017.11.091.
- Lee GA, Hwang KA, Choi KC. Inhibitory effects of 3,3’-diindolylmethane on epithelial-mesenchymal transition induced by endocrine disrupting chemicals in cellular and xenograft mouse models of breast cancer. Food Chem Toxicol 2017; 109: 284–95. doi: 10.1016/j.fct.2017.08.037.
- Wang W, Deng Z, Feng Y, Liao F, Zhou F, Feng S, et al. PM2.5 induced apoptosis in endothelial cell through the activation of the p53-bax-caspase pathway. Chemosphere 2017; 177: 135–43. doi: 10.1016/j.chemosphere.2017.02.144.
- Nabeshima K, Inoue T, Shimao Y, Sameshima T. Matrix metalloproteinases in tumor invasion: role for cell migration. Pathol Int 2002; 52: 255–64. doi: 10.1046/j.1440-1827.2002.01343.x.
- Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 1993; 75: 241–51. doi: 10.1016/0092-8674(93)80066-N.
- Jost CA, Marin MC, Kaelin WG Jr. p73 is a human p53-related protein that can induce apoptosis. Nature 1997; 389: 191–4. doi: 10.1038/38298.
- Vazquez A, Bond EE, Levine AJ, Bond GL. The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov 2008; 7: 979–87. doi: 10.1038/nrd2656.
- Kang N, Wang MM, Wang YH, Zhang ZN, Cao HR, Fan PH, et al. Tetrahydrocurcumin induces G2/M cell cycle arrest and apoptosis involving p38 MAPK activation in human breast cancer cells. Food Chem Toxicol 2014; 67: 193–200. doi: 10.1016/j.fct.2014.02.024.
- Basak P, Sadhukhan P, Sarkar P, Sil PC. Perspectives of the Nrf-2 signaling pathway in cancer progression and therapy. Toxicol Rep 2017; 4: 306–18. doi: 10.1016/j.toxrep.2017.06.002.
- Tsai CH, Shen YC, Chen HW, Liu KL, Chang JW, Fan PH, et al. Docosahexaenoic acid increases the expression of oxidative stress-induced growth inhibitor 1 through the PI3K/Akt/Nrf2 signaling pathway in breast cancer cells. Food Chem Toxicol 2017; 108: 276–88. doi: 10.1016/j.fct.2017.08.010.
- Li Y, Liu X, Rong F. PUMA mediates the apoptotic signal of hypoxia/reoxygenation in cardiomyocytes through mitochondrial pathway. Shock 2011; 35: 579–84. doi: 10.1097/SHK.0b013e318211601a.
- Ventura A, Kirsch DG, Mclaughlin ME, Tuveson DA, Grimm J, Newman J, et al. Restoration of p53 function leads to tumour regression in vivo. Nature 2007; 445: 661–5. doi: 10.1038/nature05541.
- Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 2010; 141: 52–67. doi: 10.1016/j.cell.2010.03.015.
- Yelken BO, Balci T, Susluer SY, Kayabasi C, Avci CB, Kırmızıbayrak PB, et al. The effect of tomatine on metastasis related matrix metalloproteinase (MMP) activities in breast cancer cell model. Gene 2017; 627: 408–11. doi: 10.1016/j.gene.2017.06.054.
- Jung O, Lee J, Lee YJ, Yun JM, Son YJ, Ryou C, et al. Timosaponin AIII inhibits migration and invasion of A549 human non-small-cell lung cancer cells via attenuations of MMP-2 and MMP-9 by inhibitions of ERK1/2, Src/FAK and beta-catenin signaling pathways. Bioorg Med Chem Lett 2016; 26: 3963–7. doi: 10.1016/j.bmcl.2016.07.004.
- Chen G, Yue Y, Qin J, Xiao X, Ren Q, et al. Plumbagin suppresses the migration and invasion of glioma cells via downregulation of MMP-2/9 expression and inaction of PI3K/Akt signaling pathway in vitro. J Pharmacol Sci 2017; 134: 59–67. doi: 10.1016/j.jphs.2017.04.003.
- Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002; 2: 161–174. doi: 10.1038/nrc745.
- Gotlieb WH, Saumet J, Beauchamp MC, Gu J, Lau S, Pollak MN, et al. In vitro metformin anti-neoplastic activity in epithelial ovarian cancer Gynecol Oncol 2008; 110: 246–50. doi: 10.1016/j.ygyno.2008.04.008.
- Jung JS, Jung K, Kim DH, Kim HS. Selective inhibition of MMP-9 gene expression by mangiferin in PMA-stimulated human astroglioma cells: involvement of PI3K/Akt and MAPK signaling pathways. Pharmacol Res 2012; 66: 95–103. doi: 10.1016/j.phrs.2012.02.013.
- Amin KM, Syam YM, Anwar MM, Ali HI, Abdel-Ghani TM, Serry AM, et al. Synthesis and molecular docking studies of new furochromone derivatives as p38alpha MAPK inhibitors targeting human breast cancer MCF-7 cells. Bioorg Med Chem 2017; 25: 2423–36. doi: 10.1016/j.bmc.2017.02.065.
- Dodd T, Jadhav R, Wiggins L, Stewart J, Smith E, Rocic P, et al. MMPs 2 and 9 are essential for coronary collateral growth and are prominently regulated by p38 MAPK. J Mol Cell Cardiol 2011; 51: 1015–25. doi: 10.1016/j.yjmcc.2011.08.012.
- Wang G, Li J, Zhang L, Huang S, Zhao X, Zhao X. Celecoxib induced apoptosis against different breast cancer cell lines by down-regulated NF-kappaB pathway. Biochem Biophys Res Commun 2017; 490: 969–76. doi: 10.1016/j.bbrc.2017.06.148.
- Clarke JL, Murray JB, Park BK, Copple IM. Roles of Nrf2 in drug and chemical toxicity. Curr Opin Toxicol 2016; 1: 104–10. doi: 10.1016/j.cotox.2016.10.004.
- Bobilev I, Novik V, Levi I, Shpilberg O, Levy J, Sharoni Y, et al. The Nrf2 transcription factor is a positive regulator of myeloid differentiation of acute myeloid leukemia cells. Cancer Biol Ther 2014; 11: 317–29. doi: 10.4161/cbt.11.3.14098.
- Shin DS, Kim HN, Shin KD, Yoon YJ, Kim SJ, Han DC, et al. Cryptotanshinone inhibits constitutive signal transducer and activator of transcription 3 function through blocking the dimerization in DU145 prostate cancer cells. Cancer Res 2009; 69: 193–202. doi: 10.1158/0008-5472.CAN-08-2575.
- Li W, Saud SM, Young MR, Colburn NH, Hua B. Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro. Mol Cell Biochem 2015; 406: 63–73. doi: 10.1007/s11010-015-2424-0.
- Gao AM, Ke ZP, Shi F, Sun GC, Chen H. Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway. Chem Biol Interact 2013; 206: 100–8. doi: 10.1016/j.cbi.2013.08.008.
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