Anti-cancer activity of Ginger (Zingiber officinale) leaf through the expression of activating transcription factor 3 in human colorectal cancer cells

BMC Complementary and Alternative Medicine

Jin Boo Jeong³  Hyeon Je Cho²  Jeong Rak Lee²  Kiu-Hyung Cho²  Man Hyo Lee²  Jin Wook Lee¹  Mi Kyoung Kim¹  Hyun Ji Eo¹  Hun Min Song¹  Jae Ho Park⁴  Gwang Hun Park¹ 

[1] Department of Bioresource Sciences, Andong National University, Andong 760749, South Korea;Gyeongbuk Institute for Bio-industry, Andong 760380, South Korea;Department of Medicinal Plant Resources, Andong National University, Andong 760749, South Korea;Department of Medicinal Plant Science, Jungwon University, Goesan 367805, South Korea

关键词: Colorectal cancer;    Apoptosis;    Activating transcription factor 3;    Cancer chemoprevention;    Ginger leaf;   

Others  :  1085889
DOI  :  10.1186/1472-6882-14-408

 received in 2014-06-28, accepted in 2014-10-15,  发布年份 2014

【 摘 要 】

Background

Ginger leaf (GL) has long been used as a vegetable, tea and herbal medicine. However, its pharmacological properties are still poorly understood. Thus, we performed in vitro studies to evaluate anti-cancer properties of ginger leaf and then elucidate the potential mechanisms involved.

Methods

Cell viability was measured by MTT assay. ATF3 expression level was evaluated by Western blot or RT-PCR and ATF3 transcriptional activity was determined using a dual-luciferase assay kit after the transfection of ATF3 promoter constructs. In addition, ATF3-dependent apoptosis was evaluated by Western blot after ATF3 knockdown using ATF3 siRNA.

Results

Exposure of GL to human colorectal cancer cells (HCT116, SW480 and LoVo cells) reduced the cell viability and induced apoptosis in a dose-dependent manner. In addition, GL reduced cell viability in MCF-7, MDA-MB-231 and HepG-2 cells. ATF3 knockdown attenuated GL-mediated apoptosis. GL increased activating transcription factor 3 (ATF3) expressions in both protein and mRNA level and activated ATF3 promoter activity, indicating transcriptional activation of ATF3 gene by GL. In addition, our data showed that GL-responsible sites might be between -318 and -85 region of the ATF3 promoter. We also observed that ERK1/2 inhibition by PD98059 attenuated GL-mediated ATF3 expression but not p38 inhibition by SB203580, indicating ERK1/2 pathway implicated in GL-induced ATF3 activation.

Conclusions

These findings suggest that the reduction of cell viability and apoptosis by GL may be a result of ATF3 promoter activation and subsequent increase of ATF3 expression through ERK1/2 activation in human colorectal cancer cells.

【 授权许可】

   
2014 Park et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin 2013, 63:11-30.
• [2]Wang H, Khor TO, Shu L, Su ZY, Fuentes F, Lee JH, Kong AN: Plants vs. cancer: a review on natural phytochemicals in preventing and treating cancers and their druggability. Anti-Cancer Agents Med Chem 2012, 12:1281-1305.
• [3]Yeh CT, Yen GC: Chemopreventive functions of sulforaphane: a potent inducer of antioxidant enzymes and apoptosis. J Funct Foods 2009, 1:23-32.
• [4]Rasmussen P: Ginger-Zingiber officinale Roscoe, Zingiberaceae. J Prim Health Care 2011, 3:235-236.
• [5]Eric Chan WC, Lim YY, Wong SK: Antioxidant properties of ginger leaves: an overview. Free Radic Res 2011, 1:6-16.
• [6]Lee SH, Min KW, Zhang X, Baek SJ: 3,3′-diindolylmethane induces activating transcription factor 3 (ATF3) via ATF4 in human colorectal cancer cells. J Nutr Biochem 2013, 24:664-671.
• [7]Hai T, Hartman MG: The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis. Gene 2001, 273:1-11.
• [8]Miyazaki K, Inoue S, Yamada K, Watanabe M, Liu Q, Watanabe T, Adachi MT, Tanaka Y, Kitajima S: Differential usage of alternate promoters of the human stress response gene ATF3 in stress response and cancer cells. Nucleic Acids Res 2009, 37:1438-1451.
• [9]Yin X, Dewille JW, Hai T: A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development. Oncogene 2008, 27:2118-2127.
• [10]Bottone FG Jr, Martinez JM, Alston-Mills B, Eling TE: Gene modulation by Cox-1 and Cox-2 specific inhibitors in human colorectal carcinoma cancer cells. Carcinogenesis 2004, 25:349-357.
• [11]Fan F, Jin S, Amundson SA, Tong T, Fan W, Zhao H, Zhu X, Mazzacurati L, Li X, Petrik KL, Fornace AJ Jr, Rajasekaran B, Zhan Q: ATF3 induction following DNA damage is regulated by distinct signaling pathways and over-expression of ATF3 protein suppresses cells growth. Oncogene 2002, 21:7488-7496.
• [12]Lu D, Wolfgang CD, Hai T: Activating transcription factor 3, a stress-inducible gene, suppresses Ras-stimulated tumorigenesis. J Biol Chem 2006, 281:10473-10481.
• [13]Yamaguchi K, Lee SH, Kim JS, Wimalasena J, Kitajima S, Baek SJ: Activating transcription factor 3 and early growth response 1 are the novel targets of LY294002 in a phosphatidylinositol 3-kinase-independent pathway. Cancer Res 2006, 66:2376-2384.
• [14]Allan AL, Albanese C, Pestell RG, LaMarre J: Activating transcription factor 3 induces DNA synthesis and expression of cyclin D1 in hepatocytes. J Biol Chem 2001, 276:27272-27280.
• [15]Yin X, Wolford CC, Chang YS, McConoughey SJ, Ramsey SA, Aderem A, Hai T: ATF3, an adaptive-response gene, enhances TGF{beta} signaling and cancer-initiating cell features in breast cancer cells. J Cell Sci 2010, 123:3558-3565.
• [16]Lee SH, Kim JS, Yamaguchi K, Eling TE, Baek SJ: Indole-3-carbinol and 3,3′-diindolylmethane induce expression of NAG-1 in a p53-independent manner. Biochem Bioph Res Co 2005, 328:63-69.
• [17]Lee SH, Yamaguchi K, Kim JS, Eling TE, Safe S, Park Y, Baek SJ: Conjugated linoleic acid stimulates an anti-tumorigenic protein NAG-1 in an isomer specific manner. Carcinogenesis 2006, 27:972-981.
• [18]Baek SJ, Kim JS, Jackson FR, Eling TE, McEntee MF, Lee SH: Epicatechin gallate-induced expression of NAG-1 is associated with growth inhibition and apoptosis in colon cancer cells. Carcinogenesis 2004, 25:2425-2432.
• [19]Lee SH, Bahn JH, Whitlock NC, Baek SJ: Activating transcription factor 2 (ATF2) controls tolfenamic acid-induced ATF3 expression via MAP kinase pathways. Oncogene 2010, 29:5182-5192.
• [20]Lu D, Chen J, Hai T: The regulation of ATF3 gene expression by mitogen-activated protein kinases. Biochem J 2007, 401:559-567.
• [21]Chambard JC, Lefloch R, Pouyssequr J, Lenormand P: ERK implication in cell cycle regulation. Biochim Biophys Acta 2007, 1773:1299-1310.
• [22]Xio D, Singh SV: Phenethyl isothiocyanate-induced apoptosis in p53-deficient PC-3 human prostate cancer cell line is mediated by extracellular signal-regulated kinases. Cancer Res 2002, 62:3615-3619.
• [23]Tang D, Wu D, Hirao A, Lahti JM, Liu L, Mazza B, Kidd VJ, Mak TW, Ingram AJ: ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53. J Biol Chem 2007, 277:12710-12717.
• [24]Hsu YL, Kuo OL, Lin LT, Lin CC: Asiatic acid, a triterpene, induces apoptosis and cell cycle arrest through activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways in human breast cancer cells. J Pharmacol Exp Ther 2005, 313:333-344.
• [25]Calcabrini A, Garcia-Martinez JM, Gonzalez L, Tendero MJ, Ortuno MT, Crateri P, Lopez-Rivas A, Arancia G, Gonzalez-Porque P, Martin-Perez J: Inhibition of proliferation and induction of apoptosis in human breast cancer cells by lauryl gallate. Carcinogenesis 2006, 27:1699-1712.
• [26]Liang G, Wolfgang CD, Chen BP, Chen TH, Hai T: ATF3 gene. Genomic organization, promoter, and regulation. J Biol Chem 1996, 271:1695-1701.
• [27]Cho KN, Sukhthankar M, Lee SH, Yoon JH, Baek SJ: Green tea catechin (-)-epicatechin gallate induces tumour suppressor protein ATF3 via EGR-1 activation. Eur J Cancer 2007, 43:2404-2412.
• [28]Ghasemzadeh A, Jaafar HZ, Rahmat A: Synthesis of phenolics and flavonoids in ginger (Zingiber officinale Roscoe) and their effects on photosynthesis rate. Int J Mol Sci 2011, 11:4539-4555.
• [29]Dihal AA, Tilburgs C, van Erk MJ, Rietjens IM, Woutersen RA, Stierum RH: Pathway and single gene analyses of inhibited Caco-2 differentiation by ascorbate-stabilized quercetin suggest enhancement of cellular processes associated with development of colon cancer. Mol Nutr Food Res 2007, 51:1031-1045.
• [30]Walle T, Otake Y, Walle UK, Wilson FA: Quercetin glucosides are completely hydrolyzed in ileostomy patients before absorption. J Nutr 2000, 130:2658-2661.
• [31]Crespy V, Morand C, Manach C, Besson C, Demigne C, Remesy C: Part of quercetin absorbed in the small intestine is conjugated and further secreted in the intestinal lumen. Am J Physiol 1999, 277:120-126.