Tumor Biology

, Volume 36, Issue 11, pp 8819–8829 | Cite as

Shogaol overcomes TRAIL resistance in colon cancer cells via inhibiting of survivin

  • Jung Soon Hwang
  • Hai-Chon Lee
  • Sang Cheul Oh
  • Dae-Hee Lee
  • Ki Han Kwon
Research Article


In this study, we showed the ability of representative shogaol, which as a major component of ginger, to overcome TRAIL resistance by increasing apoptosis in colon cancer cells. Shogaol increased death receptor 5 (DR5) levels. Furthermore, shogaol decreased the expression level of antiapoptotic proteins (survivin and Bcl-2) and increased pro-apoptotic protein, Bax. Shogaol treatment induced apoptosis and a robust reduction in the levels of the antiapoptotic protein survivin but did not affect the levels of many other apoptosis regulators. Moreover, knockdown of survivin sensitized colon cancer cells to resistant of TRAIL-induced apoptosis. Therefore, we showed the functions of shogaol as a sensitizing agent to induce cell death of TRAIL-resistant colon cancer cells. This study gives rise to the possibility of applying shogaol as an antitumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant colon tumor therapy.


Shogaol Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) Apoptosis Death receptor 5 (DR5) Survivin 



This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2013R1A1A4A01013550). Moreover, this study was conducted in part by research funds from Gwangju University, South Korea, in 2015.

Conflicts of interest



  1. 1.
    Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem. 1996;271:12687–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Aggarwal BB. Signalling pathways of the tnf superfamily: a double-edged sword. Nat Rev Immunol. 2003;3:745–56.CrossRefPubMedGoogle Scholar
  3. 3.
    Bellail AC, Tse MC, Song JH, Phuphanich S, Olson JJ, Sun SY, et al. DR5-mediated disc controls caspase-8 cleavage and initiation of apoptosis in human glioblastomas. J Cell Mol Med. 2010;14:1303–17.CrossRefPubMedGoogle Scholar
  4. 4.
    Krakstad C, Chekenya M. Survival signalling and apoptosis resistance in glioblastomas: opportunities for targeted therapeutics. Mol Cancer. 2010;9:135.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Oyagbemi AA, Saba AB, Azeez OI. Molecular targets of [6]-gingerol: its potential roles in cancer chemoprevention. Biofactors. 2010;36:169–78.CrossRefPubMedGoogle Scholar
  6. 6.
    Shukla Y, Singh M. Cancer preventive properties of ginger: a brief review. Food Chem Toxicol. 2007;45:683–90.CrossRefPubMedGoogle Scholar
  7. 7.
    Lee TY, Lee KC, Chen SY, Chang HH. 6-Gingerol inhibits ROS and iNOS through the suppression of PKC-alpha and NF-kappaB pathways in lipopolysaccharide-stimulated mouse macrophages. Biochem Biophys Res Commun. 2009;382:134–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Lee E, Surh YJ. Induction of apoptosis in HL-60 cells by pungent vanilloids, [6]-gingerol and [6]-paradol. Cancer Lett. 1998;134:163–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Bode AM, Ma WY, Surh YJ, Dong Z. Inhibition of epidermal growth factor-induced cell transformation and activator protein 1 activation by [6]-gingerol. Cancer Res. 2001;61:850–3.PubMedGoogle Scholar
  10. 10.
    Chakraborty D, Bishayee K, Ghosh S, Biswas R, Mandal SK. Khuda-Bukhsh AR: [6]-gingerol induces caspase 3 dependent apoptosis and autophagy in cancer cells: drug-DNA interaction and expression of certain signal genes in HeLa cells. Eur J Pharmacol. 2012;694:20–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Lee DH, Kim DW, Lee HC, Lee JH, Lee TH. Phenethyl isothiocyanate sensitizes glioma cells to TRAIL-induced apoptosis. Biochem Biophys Res Commun. 2014;446:815–21.Google Scholar
  12. 12.
    Lee SH, Cekanova M, Baek SJ. Multiple mechanisms are involved in 6-gingerol-induced cell growth arrest and apoptosis in human colorectal cancer cells. Mol Carcinog. 2008;47:197–208.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Wang S, El-Deiry WS. TRAIL and apoptosis induction by TNF-family death receptors. Oncogene. 2003;22:8628–33.CrossRefPubMedGoogle Scholar
  14. 14.
    de Wilt LH, Kroon J, Jansen G, de Jong S, Peters GJ, Kruyt FA. Bortezomib and TRAIL: a perfect match for apoptotic elimination of tumour cells? Crit Rev Oncol Hematol. 2013;85:363–72.CrossRefPubMedGoogle Scholar
  15. 15.
    Boerman RH, Anderl K, Herath J, Borell T, Johnson N, Schaeffer-Klein J, et al. The glial and mesenchymal elements of gliosarcomas share similar genetic alterations. J Neuropathol Exp Neurol. 1996;55:973–81.CrossRefPubMedGoogle Scholar
  16. 16.
    Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, RC J, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–66.CrossRefPubMedGoogle Scholar
  17. 17.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.CrossRefPubMedGoogle Scholar
  18. 18.
    Bonavia R, Inda MM, Cavenee WK, Furnari FB. Heterogeneity maintenance in glioblastoma: a social network. Cancer Res. 2011;71:4055–60.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res. 2004;64:7011–21.CrossRefPubMedGoogle Scholar
  20. 20.
    Burger PC, Vollmer RT. Histologic factors of prognostic significance in the glioblastoma multiforme. Cancer. 1980;46:1179–86.CrossRefPubMedGoogle Scholar
  21. 21.
    Hawkins CJ. Trail and malignant glioma. Vitam Horm. 2004;67:427–52.CrossRefPubMedGoogle Scholar
  22. 22.
    van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, et al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol. 2009;27:1268–74.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Rich JN, Reardon DA, Peery T, Dowel JM, Quinn JA, Penne KL, et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol. 2004;22:133–42.CrossRefPubMedGoogle Scholar
  24. 24.
    Chang SM, Wen P, Cloughesy T, Greenberg H, Schiff D, Conrad C, et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Investig New Drugs. 2005;23:357–61.CrossRefGoogle Scholar
  25. 25.
    Roth W, Isenmann S, Naumann U, Kugler S, Bahr M, Dichgans J, et al. Locoregional APO2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity. Biochem Biophys Res Commun. 1999;265:479–83.CrossRefPubMedGoogle Scholar
  26. 26.
    Saito R, Bringas JR, Panner A, Tamas M, Pieper RO, Berger MS, et al. Convection-enhanced delivery of tumor necrosis factor-related apoptosis-inducing ligand with systemic administration of temozolomide prolongs survival in an intracranial glioblastoma xenograft model. Cancer Res. 2004;64:6858–62.CrossRefPubMedGoogle Scholar
  27. 27.
    Panner A, Parsa AT, Pieper RO. Use of APO2L/TRAIL with mTOR inhibitors in the treatment of glioblastoma multiforme. Expert Rev Anticancer Ther. 2006;6:1313–22.CrossRefPubMedGoogle Scholar
  28. 28.
    Huong LD, Shin JA, Choi ES, Cho NP, Kim HM, Leem DH, et al. Beta-phenethyl isothiocyanate induces death receptor 5 to induce apoptosis in human oral cancer cells via p38. Oral Dis. 2012;18:513–9.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Division of Cosmetic Arts, Department of Culture Service, Graduate School of Culture and ArtsDongguk UniversitySeoulSouth Korea
  2. 2.Wide River Institute of ImmunologySeoul National UniversitySeoulSouth Korea
  3. 3.Division of Oncology/Hematology, Department of Internal MedicineKorea University College of MedicineSeoulSouth Korea
  4. 4.Department of Surgery and Pharmacology and Cell Biology, School of MedicineUniversity of PittsburghPittsburghUSA
  5. 5.Department of Food Science and Nutrition, College of Health, Welfare and EducationGwangju UniversityGwangjuSouth Korea
  6. 6.Division of Food Science and Nutrition, Graduate School of Biohealth ScienceGwangju UniversityGwangjuSouth Korea

Personalised recommendations