Skip to main content
SpringerLink
Log in

A combination of Citrus reticulata peel and black tea inhibits migration and invasion of liver cancer via PI3K/AKT and MMPs signaling pathway

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Liver cancer, one of the most common malignancies, is the second leading cause of cancer death in the world. The citrus reticulate peel and black tea have been studied for their beneficial health effects. In spite of the many studies have been reported, the underlying molecular mechanisms underlying its health benefits are still not fully understood. In present study, we developed a unique citrus reticulate peel black tea (CRPBT) by combined citrus reticulate peel and black tea and assessed its active ingredients, anti-oxidant and anti-liver cancer effects in vitro. The results suggested that CRPBT exhibited antioxidant capacity and effectively inhibited proliferation and migration of liver cancer cells in a dose- and time- dependent manner. Mechanistically, CRPBT significantly down-regulated phosphorylation of PI3K and AKT, and up-regulated the ratio of Bax/Bcl-2, and suppressed the expression of MMP2/9, N-cadherin and Vimetin proteins in liver cancer cells. Taken together, CRPBT has good effect on inhibiting migration, invasion, proliferation, and inducing apoptosis in liver cancer cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2):87–108. https://doi.org/10.3322/caac.21262

    Article  Google Scholar 

  2. Lai C, Frcpe F, Wu P, Prcpath Chan GC, Mrcp et al (1988) Doxorubicin versus no antitumor therapy in inoperable hepatocellular carcinoma. Cancer 62(3):479–483

    Article  CAS  Google Scholar 

  3. Hwang IT, Chung YM, Kim JJ, Chung JS, Kim BS, Kim HJ et al (2007) Drug resistance to 5-FU linked to reactive oxygen species modulator 1. Biochem Biophys Res Commun 359(2):304–310. https://doi.org/10.1016/j.bbrc.2007.05.088

    Article  CAS  PubMed  Google Scholar 

  4. Song J, Shih IM, Salani R, Chan DW, Zhang Z (2007) Annexin XI is associated with cisplatin resistance and related to tumor recurrence in ovarian cancer patients. Clin Cancer Res 13(22):6842–6849. https://doi.org/10.1158/1078-0432.CCR-07-0569

    Article  CAS  PubMed  Google Scholar 

  5. Wang XQ, Ongkeko WM, Chen L, Yang ZF, Lu P, Chen KK et al (2010) Octamer 4 (Oct4) mediates chemotherapeutic drug resistance in liver cancer cells through a potential Oct4-AKT-ATP-binding cassette G2 pathway. Hepatology 52(2):528–539. https://doi.org/10.1002/hep.23692

    Article  CAS  PubMed  Google Scholar 

  6. Kottschade L, Novotny P, Lyss A, Mazurczak M, Loprinzi C, Barton D (2016) Chemotherapy-induced nausea and vomiting: incidence and characteristics of persistent symptoms and future directions NCCTG N08C3 (Alliance). Support Care Cancer 24(6):2661–2667. https://doi.org/10.1007/s00520-016-3080-y

    Article  PubMed  PubMed Central  Google Scholar 

  7. Manohar S, Leung N (2017) Cisplatin nephrotoxicity: a review of the literature. J Nephrol 31(1):15–25. https://doi.org/10.1007/s40620-017-0392-z

    Article  CAS  PubMed  Google Scholar 

  8. Qiao G, Xu H, Li C, Li X, Farooqi A, Zhao Y et al (2018) Granulin A synergizes with cisplatin to inhibit the growth of human hepatocellular carcinoma. Int J Mol Sci 19(10):3060–3076. https://doi.org/10.3390/ijms19103060

    Article  CAS  PubMed Central  Google Scholar 

  9. Llovet JM, Bruix J (2003) Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 37(2):429–442. https://doi.org/10.1053/jhep.2003.50047

    Article  CAS  PubMed  Google Scholar 

  10. Ma L, Wen S, Zhan Y, He Y, Liu X, Jiang J (2008) Anticancer effects of the chinese medicine matrine on murine hepatocellular carcinoma cells. Planta Med 74(3):245–251. https://doi.org/10.1055/s-2008-1034304

    Article  CAS  PubMed  Google Scholar 

  11. Yang X, Wang Y, La K, Peng L, Song X, Shi X et al (2012) Inhibitory effects of cocoa tea (Camellia ptilophylla) in human hepatocellular carcinoma HepG2 in vitro and in vivo through apoptosis. J Nutr Biochem 23(9):1051–1057. https://doi.org/10.1016/j.jnutbio.2011.05.010

    Article  CAS  PubMed  Google Scholar 

  12. Yang X, Huang N (2013) Berberine induces selective apoptosis through the AMPK—mediated mitochondrial/caspase pathway in hepatocellular carcinoma. Mol Med Rep 8:505–510. https://doi.org/10.3892/mmr.2013.1506

    Article  PubMed  Google Scholar 

  13. Zhao J, Zhu J, Lv X, Xing J, Liu S, Chen C et al (2017) Curcumin potentiates the potent antitumor activity of ACNU against glioblastoma by suppressing the PI3K/AKT and NF-kappa B/COX-2 signaling pathways. OncoTargets Ther 10:5471–5482. https://doi.org/10.2147/OTT.S149708

    Article  Google Scholar 

  14. Zhou L, Yang F, Li G, Huang J, Liu Y, Zhang Q et al (2018) Coptisine induces apoptosis in human hepatoma cells through activating 67-kDa laminin receptor/cGMP signaling. Front Pharmacol 9:517–535. https://doi.org/10.3389/fphar.2018.00517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bao W, Pan H, Lu M, Ni Y, Zhang R, Gong X (2007) The apoptotic effect of sarsasapogenin from Anemarrhena asphodeloides on HepG2 human hepatoma cells. Cell Biol Int 31(9):887–892. https://doi.org/10.1016/j.cellbi.2007.02.001

    Article  CAS  PubMed  Google Scholar 

  16. Zhou Y, Li Y, Zhou T, Zheng J, Li S, Li H (2016) Dietary natural products for prevention and treatment of liver cancer. Nutrients 8(3):156–179. https://doi.org/10.3390/nu8030156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mohamed GA, Al-Abd AM, El-halawany AM, Abdallah HM, Sri M (2017) New xanthones and cytotoxic constituents from Garcinia mangostana fruit hulls against human hepatocellular, breast, and colorectal cancer celllines. J Ethnopharmacol. https://doi.org/10.1016/j.jep.2017.01.030

    Article  PubMed  Google Scholar 

  18. Fang EF, Zhang CZY, Wong JH, Shen JY, Li CH, Ng TB (2012) The MAP30 protein from bitter gourd (Momordica charantia) seeds promotes apoptosis in liver cancer cells in vitro and in vivo. Cancer Lett 324(1):66–74. https://doi.org/10.1016/j.canlet.2012.05.005

    Article  CAS  PubMed  Google Scholar 

  19. Montgomery A, Adeyeni T, San K, Heuertz RM, Ezekiel UR (2016) Curcumin sensitizes silymarin to exert synergistic anticancer activity in colon cancer cells. J Cancer 7(10):1250–1257. https://doi.org/10.7150/jca.15690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Manikandan R, Beulaja M, Arulvasu C, Sellamuthu S, Dinesh D, Prabhu D et al (2012) Synergistic anticancer activity of curcumin and catechin: an in vitro study using human cancer cell lines. Microsc Res Tech 75(2):112–116. https://doi.org/10.1002/jemt.21032

    Article  CAS  PubMed  Google Scholar 

  21. Pedan V, Rohn S, Holinger M, Hühn T, Chetschik I (2018) Bioactive compound fingerprint analysis of aged raw Pu’er tea and young ripened Pu’er tea. Molecules 23(8):1931–1949. https://doi.org/10.3390/molecules23081931

    Article  CAS  PubMed Central  Google Scholar 

  22. Yu X, Sun S, Guo Y, Liu Y, Yang D, Li G et al (2018) Citri reticulatae pericarpium (Chenpi): botany, ethnopharmacology, phytochemistry, and pharmacology of a frequently used traditional Chinese medicine. J Ethnopharmacol 220:265–282. https://doi.org/10.1016/j.jep.2018.03.031

    Article  CAS  PubMed  Google Scholar 

  23. Duan L, Dou L, Yu K, Guo L, Bai-Zhong C, Li P et al (2017) Polymethoxyflavones in peel of Citrus reticulata ‘Chachi’ and their biological activities. Food Chem. https://doi.org/10.1016/j.foodchem.2017.05.018

    Article  PubMed  Google Scholar 

  24. Lee K, Yeh M, Kao S, Hung C, Liu C, Huang Y et al (2010) The inhibitory effect of hesperidin on tumor cell invasiveness occurs via suppression of activator protein 1 and nuclear factor-kappaB in human hepatocellular carcinoma cells. Toxicol Lett 194(2):42–49. https://doi.org/10.1016/j.toxlet.2010.01.021

    Article  CAS  PubMed  Google Scholar 

  25. Hartley LC, Flowers N, Holmes J, Clarke A, Stranges S, Hooper L et al (2013) PP10 green and black tea for the primary prevention of cardiovascular disease (CVD): a cochrane systematic review. Wiley, London, pp 1–65. https://doi.org/10.1136/jech-2013-203126.109

    Book  Google Scholar 

  26. Pan H, Gao Y, Tu Y (2016) Mechanisms of body weight reduction by black tea polyphenols. Molecules 21(12):1659–1669. https://doi.org/10.3390/molecules21121659

    Article  CAS  PubMed Central  Google Scholar 

  27. Singh BN, Prateeksha Rawat AKS, Bhagat RM, Singh BR (2017) Black tea: phytochemicals, cancer chemoprevention, and clinical studies. Food Sci Nutr 57(7):1394–1410. https://doi.org/10.1080/10408398.2014.994700

    Article  CAS  Google Scholar 

  28. Naveed M, BiBi J, Kamboh AA, Suheryani I, Kakar I, Fazlani SA et al (2018) Pharmacological values and therapeutic properties of black tea (Camellia sinensis): a comprehensive overview. Biomed Pharmacother 100:521–531. https://doi.org/10.1016/j.biopha.2018.02.048

    Article  CAS  PubMed  Google Scholar 

  29. Chen Z, Lin Z (2015) Tea and human health: biomedical functions of tea active components and current issues. Biomed Biotechnol 2(16):87–102. https://doi.org/10.1631/jzus.B1500001

    Article  CAS  Google Scholar 

  30. Peluso I, Serafini M (2017) Antioxidants from black and green tea: from dietary modulation of oxidative stress to pharmacological mechanisms. Br J Pharmacol 174(11):1195–1208. https://doi.org/10.1111/bph.13649

    Article  CAS  PubMed  Google Scholar 

  31. Oak M, El Bedoui J, Schini-Kerth VB (2005) Antiangiogenic properties of natural polyphenols from red wine and green tea. J Nutr Biochem 16(1):1–8. https://doi.org/10.1016/j.jnutbio.2004.09.004

    Article  CAS  PubMed  Google Scholar 

  32. Rodriguez SK, Guo W, Liu L, Band MA, Paulson EK, Meydani M (2006) Green tea catechin, epigallocatechin-3-gallate, inhibits vascular endothelial growth factor angiogenic signaling by disrupting the formation of a receptor complex. Int J Cancer 118(7):1635–1644. https://doi.org/10.1002/ijc.21545

    Article  CAS  PubMed  Google Scholar 

  33. Fassina G, Venè R, Morini M (2004) Mechanisms of inhibition of tumor angiogenesis and vascular tumor growth by epigallocatechin-3-gallate. Clin Cancer Res 10:4865–4873

    Article  CAS  Google Scholar 

  34. Lee WJ (2005) Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Mol Pharmacol 68(4):1018–1030. https://doi.org/10.1124/mol.104.008367

    Article  CAS  PubMed  Google Scholar 

  35. Yang CS, Lambert JD, Hou Z, Ju J, Lu G, Hao X (2006) Molecular targets for the cancer preventive activity of tea polyphenols. Mol Carcinog 45(6):431–435. https://doi.org/10.1002/mc.20228

    Article  CAS  PubMed  Google Scholar 

  36. Dias PM, Changarath J, Damodaran A, Joshi MK (2014) Compositional variation among black tea across geographies and their potential influence on endothelial nitric oxide and antioxidant activity. J Agric Food Chem 62(28):6655–6668. https://doi.org/10.1021/jf501611w

    Article  CAS  PubMed  Google Scholar 

  37. Yao L, Liu X, Jiang Y, Caffin N, D’Arcy B, Singanusong R et al (2006) Compositional analysis of teas from Australian supermarkets. Food Chem 94(1):115–122. https://doi.org/10.1016/j.foodchem.2004.11.009

    Article  CAS  Google Scholar 

  38. Akuli A, Pal A, Joshi R, Gulati A, Dey T, Bhattacharyya N (2012) A new method for rapid detection of total colour (TC), theaflavins (TF), thearubigins (TR) and brightness (TB) in orthodox teas. International Conference on Sensing Technology (ICST); 2012 2012-01-01: IEEE; 2012. pp 23–28

  39. Batsalova T, Basheva D, Bardarov K, Bardarov V, Dzhambazov B, Teneva I (2018) Assessment of the cytotoxicity, antioxidant activity and chemical composition of extracts from the cyanobacterium Fischerella major Gomont. Chemosphere. https://doi.org/10.1016/j.chemosphere.2018.11.097

    Article  PubMed  Google Scholar 

  40. Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C (1999) Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic Biol Med 26(9):1231–1237

    Article  CAS  Google Scholar 

  41. Wang X, Lan Y, Zhu Y, Li S, Liu M, Song X et al (2018) Hepatoprotective effects of Auricularia cornea var. Li. polysaccharides against the alcoholic liver diseases through different metabolic pathways. Sci Rep 8(1):1–12. https://doi.org/10.1038/s41598-018-25830-w

    Article  CAS  Google Scholar 

  42. Tong J, Wang Z (2017) Analysis of epidermal growth factor receptor-induced cell motility by wound healing assay. Methods Mol Biol (Clifton, NJ) 1652:159–163. https://doi.org/10.1007/978-1-4939-7219-7_12

    Article  CAS  Google Scholar 

  43. Dhanasekaran R, Bandoh S, Roberts LR (2016) Molecular pathogenesis of hepatocellular carcinoma and impact of therapeutic advances. F1000Research 5:876–894. https://doi.org/10.12688/f1000research.6946.1

    Article  CAS  Google Scholar 

  44. Friedman M, Mackey BE, Kim H, Lee I, Lee K, Lee S et al (2007) Structure-activity relationships of tea compounds against human cancer cells. J Agric Food Chem 55(2):243–253. https://doi.org/10.1021/jf062276h

    Article  CAS  PubMed  Google Scholar 

  45. Kuo P, Lin C (2003) Green tea constituent (−)-epigallocatechin-3-gallate inhibits HepG2 cell proliferation and induces apoptosis through p53-dependent and fas-mediated pathways. J Biomed Sci 10(2):219–227. https://doi.org/10.1159/000068711

    Article  CAS  PubMed  Google Scholar 

  46. Shirakami Y, Shimizu M, Adachi S, Sakai H, Nakagawa T, Yasuda Y et al (2009) (−)-Epigallocatechin gallate suppresses the growth of human hepatocellular carcinoma cells by inhibiting activation of the vascular endothelial growth factor-vascular endothelial growth factor receptor axis. Cancer Sci 100(10):1957–1962. https://doi.org/10.1111/j.1349-7006.2009.01241.x

    Article  CAS  PubMed  Google Scholar 

  47. Yumnam S, Hong GE, Raha S, Saralamma VVG, Lee HJ, Lee W et al (2016) Mitochondrial dysfunction and Ca2+ overload contributes to hesperidin induced paraptosis in hepatoblastoma cells, HepG2. J Cell Physiol 231(6):1261–1268. https://doi.org/10.1002/jcp.25222

    Article  CAS  PubMed  Google Scholar 

  48. Rice-Evans CA, Miller NJ, Paganga G (1997) Antioxidant properties of phenolic compounds. Trends Plant Sci 4(2):152–159

    Article  Google Scholar 

  49. Lee S, Im K, Suh S, Jung J (2003) Protective effect of green tea polyphenol (-)-epigallocatechin gallate and other antioxidants on lipid peroxidation in gerbil brain homogenates. Phytother Res 17(3):206–209. https://doi.org/10.1002/ptr.1090

    Article  CAS  PubMed  Google Scholar 

  50. Ma L, Wang J, Lin J, Pan Q, Yu Y, Sun F (2014) Cluster of differentiation 166 (CD166) regulated by phosphatidylinositide 3-kinase (PI3K)/AKT signaling to exert its anti-apoptotic role via yes-associated protein (YAP) in liver cancer. J Biol Chem 289(10):6921–6933. https://doi.org/10.1074/jbc.M113.524819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhu M, Li W, Lu Y, Dong X, Lin B, Chen Y et al (2017) HBx drives alpha fetoprotein expression to promote initiation of liver cancer stem cells through activating PI3K/AKT signal pathway. Int J Cancer 140(6):1346–1355. https://doi.org/10.1002/ijc.30553

    Article  CAS  PubMed  Google Scholar 

  52. Feng Y, Zu L, Zhang L (2018) MicroRNA-26b inhibits the tumor growth of human liver cancer through the PI3K/Akt and NF-κB/MMP-9/VEGF pathways. Oncol Rep 39(5):2288–2296. https://doi.org/10.3892/or.2018.6289

    Article  CAS  PubMed  Google Scholar 

  53. Li Y, Zheng-ming Xiao-tong S, Ping Y, Wang FX (2016) The effects of urotensin ii on migration and invasion are mediated by NADPH oxidase-derived reactive oxygen species through the c-jun n-terminal kinase pathway in human hepatoma cells. Peptides. https://doi.org/10.1016/j.peptides.2016.12.005

    Article  PubMed  Google Scholar 

  54. Pittayapruek P, Meephansan J, Prapapan O, Komine M, Ohtsuki M (2016) Role of matrix metalloproteinases in photoaging and photocarcinogenesis. Int J Mol Sci 17(6):868–888. https://doi.org/10.3390/ijms17060868

    Article  CAS  PubMed Central  Google Scholar 

  55. Li H, Wang H, Ren Z (2018) MicroRNA-214-5p inhibits the invasion and migration of hepatocellular carcinoma cells by targeting Wiskott-Aldrich syndrome like. Cell Physiol Biochem 46(2):757–764. https://doi.org/10.1159/000488734

    Article  CAS  PubMed  Google Scholar 

  56. Zheng Q, Chen X, Bao Q, Yu J, Chen L (2018) ILK enhances migration and invasion abilities of human endometrial stromal cells by facilitating the epithelial-mesenchymal transition. Gynecol Endocrinol. https://doi.org/10.1080/09513590.2018.1498477

    Article  PubMed  Google Scholar 

  57. Shi Y, Wu Q, Xuan W, Feng X, Wang F, Tsao BP et al (2018) Transcription factor SOX5 promotes the migration and invasion of fibroblast-like synoviocytes in part by regulating MMP-9 expression in collagen-induced arthritis. Front Immunol 9:749–760. https://doi.org/10.3389/fimmu.2018.00749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81803236, 31800295, 81903319). Guangdong Science and Technology program (Nos. 2017A070702004, 2016B090918118, 2017A020224015, 2018KJYZ002), Natural Science Foundation of Guangdong Province (Nos. 2017A030310504 and 2016A030313006), ShaoGuan Science and Technology Program (No. 2018CS11902), Science and Technology Board of Yingde (NO. JHXM2018029), the Foundation for Department of Education of Guangdong Province (Nos. 2016KCXTD005 and 2017KSYS010), the Youth Foundation of Wuyi University (No. 2017td01), the President Foundation of Guangdong Academy of Agricultural Sciences (Nos. 201534 and 201720).

Author information

Author notes

  1. Shuai Wen and Lingli Sun have contributed equally to this work.

Authors and Affiliations

  1. School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, 529020, People’s Republic of China

    Shuai Wen, Ran An, Mengen Huo & Dongli Li

  2. Tea Research Institute, Guangdong Academy of Agricultural Sciences/Guangdong Key Laboratory of Tea Resources Innovation & Utilization, Guangzhou, 510640, People’s Republic of China

    Lingli Sun, Wenji Zhang, Limin Xiang, Qiuhua Li, Xingfei Lai & Shili Sun

  3. International Healthcare Innovation Institute (Jiangmen), Jiangmen, 529040, People’s Republic of China

    Dongli Li

Authors
  1. Shuai Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lingli Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ran An
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenji Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Limin Xiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qiuhua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xingfei Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mengen Huo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dongli Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shili Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SS and DL conceived and designed the experiments. SW performed the experiments. SW and LS analyzed the data. LX, WZ, XL, QL, RA and MH contributed reagents. SW wrote the paper, and LS and SS critically revised the manuscript. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Dongli Li or Shili Sun.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 850 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wen, S., Sun, L., An, R. et al. A combination of Citrus reticulata peel and black tea inhibits migration and invasion of liver cancer via PI3K/AKT and MMPs signaling pathway. Mol Biol Rep 47, 507–519 (2020). https://doi.org/10.1007/s11033-019-05157-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-019-05157-z

Keywords

Search

Navigation