Advertisement

Tumor Biology

, Volume 35, Issue 8, pp 7467–7474 | Cite as

Antimetastatic effects of licochalcone A on oral cancer via regulating metastasis-associated proteases

  • Huan Shen
  • Guang Zeng
  • Guo Tang
  • Xingwei Cai
  • Lixia Bi
  • Changcheng Huang
  • Yongjin Yang
Research Article

Abstract

Licochalcone A, a major phenolic constituent of the licorice species Glycyrrhiza inflata, has been proven to possess various biological benefits including anti-cancer activity. However, the detailed effects and molecular mechanisms of licochalcone A on the invasiveness and metastasis of oral cancer cells have not been fully understood. Thus, SCC-25 oral cancer cells were subjected to a treatment with licochalcone A at indicated concentrations (25, 50, and 100 μg/mL) for 36 h and then analyzed for the effect of licochalcone A on the cell migration and invasion. In vitro assays, including wound healing, cell adhesion, and cell invasion/migration assays, revealed that licochalcone A treatment significantly inhibited the cell migration/invasion capacities of SCC-25 cells. Also, results of zymography and Western blotting showed that activity and protein level of matrix metalloproteinase-2 (MMP-2) was suppressed, but TIMP-2 level was increased, indicating the important role of MMP-2 and TIPM-2 in anti-metastatic regulation of SCC-25 cells. Furthermore, licochalcone A was shown to suppress the nuclear factor-kappa B (NF-κB) signal, as evidenced by the decreased expression of phosphorylated p65 (p-65) protein in licochalcone A-treated SCC-25 cells. Notably, we also found that licochalcone A treatment increased the expression of the epithelial marker E-cadherin and decreased the expression of mesenchymal markers N-cadherin in SCC-25 cells. This is the first report describing the effects and possible mechanisms of licochalcone A on tumor invasion and metastasis of SCC-25 cells. Taken together, our findings support that licochalcone A can be developed to a potent anti-metastatic candidate for oral cancer therapy.

Keywords

Licochalcone A Oral cancer Invasion Migration Metastasis MMP-2 TIMP-2 E-cadherin N-cadherin p-p65 

Notes

Conflicts of interest

None.

References

  1. 1.
    Spiro RH, Alfonso AE, Farr HW, Strong EW. Cervical node metastasis from epidermoid carcinoma of the oral cavity and oropharynx. A critical assessment of current staging. Am J Surg. 1974;128:562–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45:309–16.PubMedCrossRefGoogle Scholar
  3. 3.
    Johnson NW, Warnakulasuriya S, Gupta PC, Dimba E, Chindia M, Otoh EC, et al. Global oral health inequalities in incidence and outcomes for oral cancer: causes and solutions. Adv Dent Res. 2011;23:237–46.PubMedCrossRefGoogle Scholar
  4. 4.
    Scully C, Bagan J. Oral squamous cell carcinoma overview. Oral Oncol. 2009;45:301–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Myoung H, Hong SP, Yun PY, Lee JH, Kim MJ. Anti-cancer effect of genistein in oral squamous cell carcinoma with respect to angiogenesis and in vitro invasion. Cancer Sci. 2003;94:215–20.PubMedCrossRefGoogle Scholar
  6. 6.
    Weiss L. Metastatic inefficiency. Adv Cancer Res. 1990;54:159–211.PubMedCrossRefGoogle Scholar
  7. 7.
    Fidler IJ. Tumor heterogeneity and the biology of cancer invasion and metastasis. Cancer Res. 1978;38:2651–60.PubMedGoogle Scholar
  8. 8.
    Chambers AF, MacDonald IC, Schmidt EE, Morris VL, Groom AC. Clinical targets for anti-metastasis therapy. Adv Cancer Res. 2000;79:91–121.PubMedCrossRefGoogle Scholar
  9. 9.
    Price JT, Thompson EW. Mechanisms of tumour invasion and metastasis: emerging targets for therapy. Expert Opin Ther Targets. 2002;6:217–33.PubMedCrossRefGoogle Scholar
  10. 10.
    Ha KT, Kim JK, Lee YC, Kim CH. Inhibitory effect of Daesungki-Tang on the invasiveness potential of hepatocellular carcinoma through inhibition of matrix metalloproteinase-2 and -9 activities. Toxicol Appl Pharmacol. 2004;200:1–6.PubMedCrossRefGoogle Scholar
  11. 11.
    Yang S, Chen J, Guo Z, Xu XM, Wang L, Pei XF, et al. Triptolide inhibits the growth and metastasis of solid tumors. Mol Cancer Ther. 2003;2:65–72.PubMedGoogle Scholar
  12. 12.
    Ho ML, Hsieh YS, Chen JY, Chen KS, Chen JJ, Kuo WH, et al. Antimetastatic potentials of Dioscorea nipponica on melanoma in vitro and in vivo. Evid Based Complement Alternat Med. 2011;2011:507920. doi: 10.1155/2011/507920.PubMedCentralPubMedGoogle Scholar
  13. 13.
    Yang SF, Chen MK, Hsieh YS, Yang JS, Zavras AI, Hsieh YH, et al. Antimetastatic effects of Terminalia catappa L. on oral cancer via a down-regulation of metastasis-associated proteases. Food Chem Toxicol. 2010;48:1052–8.PubMedCrossRefGoogle Scholar
  14. 14.
    Yang SF, Yang WE, Kuo WH, Chang HR, Chu SC, Hsieh YS. Antimetastatic potentials of flavones on oral cancer cell via an inhibition of matrix-degrading proteases. Arch Oral Biol. 2008;53:287–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Lu KV, Jong KA, Rajasekaran AK, Cloughesy TF, Mischel PS. Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line. Lab Invest. 2004;84:8–20.PubMedCrossRefGoogle Scholar
  16. 16.
    Yarrow JC, Perlman ZE, Westwood NJ, Mitchison TJ. A high-throughput cell migration assay using scratch wound healing, a comparison of image-based readout methods. BMC Biotechnol. 2004;4:21.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Simeone AM, McMurtry V, Nieves-Alicea R, Saavedra JE, Keefer LK, Johnson MM, et al. TIMP-2 mediates the anti-invasive effect of the nitric oxide-releasing prodrug JS-K in breast cancer cells. Breast Cancer Res. 2008;10:R44.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    White CD, Brown MD, Sacks DB. IQGAPs in cancer: a family of scaffold proteins underlying tumorigenesis. FEBS Lett. 2009;583:1817–24.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer. 2009;9:361–71.PubMedCrossRefGoogle Scholar
  20. 20.
    Auwardt RB, Mudge SJ, Chen C, Power DA. Inhibition with antisense oligonucleotide suggests that IkappaB-alpha does not form a negative autoregulatory loop for NF-kappaB in mesangial cells. Exp Nephrol. 2000;8:144–51.PubMedCrossRefGoogle Scholar
  21. 21.
    Micalizzi DS, Farabaugh SM, Ford HL. Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia. 2010;15:117–34.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Harlozinska A. Progress in molecular mechanisms of tumor metastasis and angiogenesis. Anticancer Res. 2005;25:3327–33.PubMedGoogle Scholar
  23. 23.
    Zell JA, Ou SH, Ziogas A, Anton-Culver H. Survival improvements for advanced stage non-bronchioloalveolar carcinoma-type non-small-cell lung cancer cases with Ipsilateral intrapulmonary metastasis. Cancer. 2008;112:136–43.PubMedCrossRefGoogle Scholar
  24. 24.
    Coussens LM, Werb Z. Matrix metalloproteinases and the development of cancer. Chem Biol. 1996;3:895–904.PubMedCrossRefGoogle Scholar
  25. 25.
    Lu KW, Chen JC, Lai TY, Yang JS, Weng SW, Ma YS, et al. Gypenosides inhibits migration and invasion of human oral cancer SAS cells through the inhibition of matrix metalloproteinase-2–9 and urokinase-plasminogen by ERK1/2 and NF-kappa B signaling pathways. Hum Exp Toxicol. 2011;30:406–15.PubMedCrossRefGoogle Scholar
  26. 26.
    Chien MH, Ying TH, Hsieh YS, Chang YC, Yeh CM, Ko JL, et al. Dioscorea nipponica Makino inhibits migration and invasion of human oral cancer HSC-3 cells by transcriptional inhibition of matrix metalloproteinase-2 through modulation of CREB and AP-1 activity. Food Chem Toxicol. 2012;50:558–66.PubMedCrossRefGoogle Scholar
  27. 27.
    Guruvayoorappan C, Kuttan G. Amentoflavone inhibits experimental tumor metastasis through a regulatory mechanism involving MMP-2, MMP-9, prolyl hydroxylase, lysyl oxidase, VEGF, ERK-1, ERK-2, STAT-1, NM23 and cytokines in lung tissues of C57BL/6 mice. Immunopharmacol Immunotoxicol. 2008;30:711–27.PubMedCrossRefGoogle Scholar
  28. 28.
    Farina AR, Coppa A, Tiberio A, Tacconelli A, Turco A, Colletta G, et al. Transforming growth factor-beta1 enhances the invasiveness of human MDA-MB-231 breast cancer cells by up-regulating urokinase activity. Int J Cancer. 1998;75:721–30.PubMedCrossRefGoogle Scholar
  29. 29.
    Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.PubMedCrossRefGoogle Scholar
  30. 30.
    Paul S, DeCastro AJ, Lee HJ, Smolarek AK, So JY, Simi B, et al. Dietary intake of pterostilbene, a constituent of blueberries, inhibits the β-catenin/p65 downstream signaling pathway and colon carcinogenesis in rats. Carcinogenesis. 2010;31:1272–8.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Liu M, Sakamaki T, Casimiro MC, Willmarth NE, Quong AA, Ju X, et al. The canonical NF-κB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion. Cancer Res. 2010;70:10464–73.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Ahmad A, Wang Z, Kong D, Ali R, Ali S, Banerjee S, et al. Platelet-derived growth factor-D contributes to aggressiveness of breast cancer cells by up-regulating Notch and NF-κB signaling pathways. Breast Cancer Res Treat. 2011;126:15–25.PubMedCrossRefGoogle Scholar
  33. 33.
    Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–54.PubMedCrossRefGoogle Scholar
  34. 34.
    Yao D, Dai C, Peng S. Mechanism of the mesenchymal–epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res. 2011;9:1608–20.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Huan Shen
    • 1
  • Guang Zeng
    • 2
  • Guo Tang
    • 3
  • Xingwei Cai
    • 1
  • Lixia Bi
    • 1
  • Changcheng Huang
    • 1
  • Yongjin Yang
    • 1
  1. 1.Department of StomatologyThe General Hospital of the Second Artillery Corps of Chinese PLABeijingPeople’s Republic of China
  2. 2.Department of Plastic and Burn Surgery, Tangdu HospitalThe Fourth Military Medical UniversityXi’anPeople’s Republic of China
  3. 3.Department of DermatologyThe First Affiliated Hospital of the General Hospital of the People’s Liberation ArmyBeijingPeople’s Republic of China

Personalised recommendations