Abstract
β-Ionone is an end ring analog of β-carotenoid which has been shown to possess potent anti-proliferative activity both in vitro and in vivo. To investigate the possible inhibitory effects of β-ionone, we studied cell growth characteristics, DNA synthesis, cell cycle progression, as well as mitogen-activated protein kinases (MAPKs) pathways in the human gastric adenocarcinoma cancer cell line (SGC-7901). Our results show that cell growth and DNA synthesis were inhibited, and the cell cycle was arrested at the G0/G1 phase in a dose-dependent manner in cells treated with β-ionone (25, 50, 100 and 200 μmol/L) for 24 h. We found that the β-ionone significantly decreased the extracellular signal-regulated kinase protein expression and significantly increased the levels of p38 and Jun-amino-terminal kinase protein expression (P < 0.01). β-Ionone also inhibited cell cycle-related proteins of Cdk4, Cyclin B1, D1 and increased p27 protein expression in SGC-7901 cells. These results suggested that the cell cycle arrest observed may be regulated through a MAPK pathway by transcriptional down-regulation of cell cycle proteins. These results demonstrate potent ability of β-ionone to arrest cell cycle of SGC-7901 cells and decrease proliferation.
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Asokkumar S, Naveenkumar C, Raghunandhakumar S et al (2011) Antiproliferative and antioxidant potential of β-ionone against benzo(a)pyrene-induced lung carcinogenesis in Swiss albino mice. Mol Cell Biochem 363(1–2):335–345
Cardozo MT, de Conti A, Ong TP et al (2011) Chemopreventive effects of β-ionone and geraniol during rat hepatocarcinogenesis promotion: distinct actions on cell proliferation, apoptosis, HMGCoA reductase, and RhoA. J Nutr Biochem 22(2):130–135
Chen BQ, Xue YB, Liu JR et al (2003) Inhibition of conjugated linoleic acid on mouse forestomach neoplasia induced by benzo (a) pyrene and chemopreventive mechanisms. World J Gastroenterol 9(1):44–49
Chen HS, Liu M, Shi LJ et al (2011) Effects of raspberry phytochemical extract on cell proliferation, apoptosis, and serum proteomics in a rat model. J Food Sci 76(8):T192–T198
Chu IM, Hengst L, Slingerland JM (2008) The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer 8(4):253–267
Dhillon AS, Hagan S, Rath O, Kolch W (2007) MAP kinase signalling pathways in cancer. Oncogene 26(22):3279–3290
Doll R, Peto R (1981) The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 66(6):1191–1308
Donovan N, Becker EB, Konishi Y, Bonni A (2002) JNK phosphorylation and activation of BAD couples the stress-activated signaling pathway to the cell death machinery. J Biol Chem 277(43):40944–40949
Duncan RE, Lau D, El-Sohemy A, Archer MC (2004) Geraniol and β-ionone inhibit proliferation, cell cycle progression, and cyclin-dependent kinase 2 activity in MCF-7 breast cancer cells independent of effects on HMG-CoA reductase activity. Biochem Pharmacol 68(9):1739–1747
Elson CE, Yu SG (1994) The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables. J Nutr 124(5):607–614
Feakins RM, Nickols CD, Bidd H, Walton SJ (2003) Abnormal expression of pRb, p16, and cyclin D1 in gastric adenocarcinoma and its lymph node metastases: relationship with pathological features and survival. Hum Pathol 34(12):1276–1282
Haagenson KK, Wu GS (2010) Mitogen activated protein kinase phosphatases and cancer. Cancer Biol Ther 9(5):337–340
He L, Mo H, Hadisusilo S, Qureshi AA, Elson CE (1997) Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. J Nutr 127(5):668–674
Helin K (1998) Regulation of cell proliferation by the E2F transcription factors. Curr Opin Genet Dev 8(1):28–35
Huang CS, Lyu SC, Hu ML (2012) Synergistic effects of the combination of β-ionone and sorafenib on metastasis of human hepatoma SK-Hep-1 cells. Invest New Drugs 30(4):1449–1459
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. doi:10.3322/caac.20107
Kim MO, Moon DO, Kang CH, Kwon TK, Choi YH, Kim GY (2010) β-Ionone enhances TRAIL-induced apoptosis in hepatocellular carcinoma cells through Sp1-dependent upregulation of DR5 and downregulation of NF-kappaB activity. Mol Cancer Ther 9(4):833–843. doi:10.1158/1535-7163.MCT-09-0610
Langenfeld J, Kiyokawa H, Sekula D, Boyle J, Dmitrovsky E (1997) Posttranslational regulation of cyclin D1 by retinoic acid: a chemoprevention mechanism. Proc Natl Acad Sci USA 94(22):12070–12074
Lei K, Nimnual A, Zong WX et al (2002) The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase. Mol Cell Biol 22(13):4929–4942
Li W, Mei X, Tu YY (2012) Effects of tea polyphenols and their polymers on MAPK signaling pathways in cancer research. Mini Rev Med Chem 12(2):120–126
Lim U, Song MA (2012) Dietary and lifestyle factors of DNA methylation. Methods Mol Biol 863:359–376
Liu JR, Chen BQ, Yang BF et al (2004a) Apoptosis of human gastric adenocarcinoma cells induced by β-ionone. World J Gastroenterol 10(3):348–351
Liu JR, Yang BF, Chen BQ, Yang YM, Dong HW, Song YQ (2004b) Inhibition of β-ionone on SGC-7901 cell proliferation and upregulation of metalloproteinases-1 and -2 expression. World J Gastroenterol 10(2):167–171
Liu JR, Yang YM, Dong HW, Sun XR (2005) [Effect of β-ionone in human mammary cancer cells (Er−) by MAPK pathway]. J Hyg Res 34(6):706–709
Liu JR, Sun XR, Dong HW et al (2008) β-Ionone suppresses mammary carcinogenesis, proliferative activity and induces apoptosis in the mammary gland of the Sprague–Dawley rat. Int J Cancer 122(12):2689–2698
Liu JR, Dong HW, Chen BQ, Zhao P, Liu RH (2009a) Fresh apples suppress mammary carcinogenesis and proliferative activity and induce apoptosis in mammary tumors of the Sprague–Dawley rat. J Agric Food Chem 57(1):297–304
Liu M, Lin LQ, Song BB et al (2009b) Cranberry phytochemical extract inhibits SGC-7901 cell growth and human tumor xenografts in Balb/c nu/nu mice. J Agric Food Chem 57(2):762–768
Liu JR, Dong HW, Sun XR et al (2010a) Effects of β-ionone on mammary carcinogenesis and antioxidant status in rats treated with DMBA. Nutr Cancer 62(1):58–65
Liu Y, Liu M, Li B et al (2010b) Fresh raspberry phytochemical extract inhibits hepatic lesion in a Wistar rat model. Nutr Metab 7:84
Liu Q, Dong HW, Sun WG et al (2013) Apoptosis initiation of β-ionone in SGC-7901 gastric carcinoma cancer cells via a PI3K-AKT pathway. Arch Toxicol 87(3):481–490. doi:10.1007/s00204-012-0962-8
MacCorkle RA, Tan TH (2005) Mitogen-activated protein kinases in cell-cycle control. Cell Biochem Biophys 43(3):451–461
Mercer WE (1998) Checking on the cell cycle. J Cell Biochem Suppl 30–31:50–54
Mo H, Elson CE (1999) Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids. J Nutr 129(4):804–813
Murray CJ, Lopez AD (1997) Mortality by cause for eight regions of the world: global Burden of Disease Study. Lancet 349(9061):1269–1276
Nagini S (2012) Carcinoma of the stomach: a review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol 4(7):156–169
Nguyen Ngoc TD, Son YO, Lim SS et al (2012) Sodium fluoride induces apoptosis in mouse embryonic stem cells through ROS-dependent and caspase- and JNK-mediated pathways. Toxicol Appl Pharmacol 259(3):329–337. doi:10.1016/j.taap.2012.01.010
Rajendran P, Ho E, Williams DE, Dashwood RH (2011) Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells. Clin Epigenet 3(1):4
Semczuk A, Jakowicki JA (2004) Alterations of pRb1-cyclin D1-cdk4/6-p16(INK4A) pathway in endometrial carcinogenesis. Cancer Lett 203(1):1–12
Senore C, Giordano L, Bellisario C, Di Stefano F, Segnan N (2012) Population based cancer screening programmes as a teachable moment for primary prevention interventions. A review of the literature. Front Oncol 2:45
Sherr CJ (1995) D-type cyclins. Trends Biochem Sci 20(5):187–190
Steelman LS, Franklin RA, Abrams SL et al (2011) Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy. Leukemia 25(7):1080–1094. doi:10.1038/leu.2011.66
Torii S, Yamamoto T, Tsuchiya Y, Nishida E (2006) ERK MAP kinase in G cell cycle progression and cancer. Cancer Sci 97(8):697–702
Vieira A, Heidor R, Cardozo MT et al (2011) Efficacy of geraniol but not of β-ionone or their combination for the chemoprevention of rat colon carcinogenesis. Braz J Med Biol Res 44(6):538–545 Revista brasileira de pesquisas medicas e biologicas/Sociedade Brasileira de Biofisica [et al]
Wang H, Gao GH, Prior RL (1996) Total antioxidant capacity of fruits. J Agric Food Chem 44:701–705
Willett WC (2002) Balancing life-style and genomics research for disease prevention. Science 296(5568):695–698
Yamamoto T, Ebisuya M, Ashida F, Okamoto K, Yonehara S, Nishida E (2006) Continuous ERK activation downregulates antiproliferative genes throughout G1 phase to allow cell-cycle progression. Curr Biol 16(12):1171–1182
Yu Q, Geng Y, Sicinski P (2001) Specific protection against breast cancers by cyclin D1 ablation. Nature 411(6841):1017–1021
Zhang W, Liu HT (2002) MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res 12(1):9–18
Zhang Y, Yao S, Li J (2006) Vegetable-derived isothiocyanates: anti-proliferative activity and mechanism of action. Proc Nutr Soc 65(1):68–75
Acknowledgments
This research was supported by the National Natural Science Fund (No. 30200229 and 30772511), HeiLongJiang Postdoctoral Fund (No. LRB03-000120), planning program of key problems from Sanitation Bureau of Heilongjiang province (No. 2007-470), and Department of Education, HeiLongJiang Province (No. 12521274), People’s Republic of China. Hong-Wei Dong, Shuang Zhang and Wen-Guang Sun are co-first authors. Jia-Ren Liu and Ming-Song Li are co-corresponding authors. There are no conflicts of interest in this study.
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Hong-Wei Dong, Shuang Zhang, Wen-Guang Sun and Qian Liu are co-first authors.
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Dong, HW., Zhang, S., Sun, WG. et al. β-Ionone arrests cell cycle of gastric carcinoma cancer cells by a MAPK pathway. Arch Toxicol 87, 1797–1808 (2013). https://doi.org/10.1007/s00204-013-1041-5
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DOI: https://doi.org/10.1007/s00204-013-1041-5