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Archives of Pharmacal Research

, Volume 38, Issue 11, pp 2042–2048 | Cite as

Naringenin enhances NK cell lysis activity by increasing the expression of NKG2D ligands on Burkitt’s lymphoma cells

  • Jeong Hwa Kim
  • Jae Kwon LeeEmail author
Research Article

Abstract

Natural killer (NK) cells are capable of identifying and killing tumor cells as well as virus infected cells without pre-sensitization. NK cells express activating and inhibitory receptors, and can distinguish between normal and tumor cells. The present study was designed to demonstrate the importance of the expression level of NKG2D ligands on the Burkitt’s lymphoma cell line, Raji, in enhancing NK cell cytolytic activity. Various flavonoids were used as stimulants to enhance the expression of NKG2D ligands. NK cell lysis activity against Raji was not changed by pre-treatment of Raji with luteolin, kaempferol, taxifolin and hesperetin. However, treatment of Raji with naringenin showed increased sensitivity to NK cell lysis than untreated control cells. The activity of naringenin was due to enhanced NKG2D ligand expression. These results provide evidence that narigenin’s antitumor activity may be due to targeting of NKG2D ligand expression and suggests a possible immunotherapeutic role for cancer treatment.

Keywords

Natural killer cell Naringenin NKG2D ligands Raji Flavonoid 

References

  1. Armeanu, S., M. Bitzer, U.M. Lauer, S. Venturelli, A. Pathil, M. Krusch, S. Kaiser, J. Jobst, I. Smirnow, A. Wagner, A. Steinle, and H.R. Salih. 2005. Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Research 65: 6321–6329.CrossRefPubMedGoogle Scholar
  2. Bae, D.S., Y.K. Hwang, and J.K. Lee. 2012. Importance of NKG2D-NKG2D ligands interaction for cytolytic activity of natural killer cell. Cellular Immunology 276: 122–127.CrossRefPubMedGoogle Scholar
  3. Bae, J.H., J.Y. Kim, M.J. Kim, S.H. Chang, Y.S. Park, C.H. Son, S.J. Park, J.S. Chung, E.Y. Lee, S.H. Kim, and C.D. Kang. 2010. Quercetin enhances susceptibility to NK cell-mediated lysis of tumor cells through induction of NKG2D ligands and suppression of HSP70. Journal of Immunotherapy 33: 391–401.CrossRefPubMedGoogle Scholar
  4. Barnes, S., J. Prasain, T. D’alessandro, A. Arabshahi, N. Botting, M.A. Lila, G. Jackson, E.M. Janle, and C.M. Weaver. 2011. The metabolism and analysis of isoflavones and other dietary polyphenols in foods and biological systems. Food and Function 2: 235–244.PubMedCentralCrossRefPubMedGoogle Scholar
  5. Conejo-Garcia, J.R., F. Benencia, M.C. Courreges, P.A. Gimotty, E. Khang, R.J. Buckanovich, K.A. Frauwirth, L. Zhang, D. Katsaros, C.B. Thompson, B. Levine, and G. Coukos. 2004. Ovarian carcinoma expresses the NKG2D ligand Letal and promotes the survival and expansion of CD28- antitumor T cells. Cancer Research 64: 2175–2182.CrossRefPubMedGoogle Scholar
  6. Davis, J.M., E.A. Murphy, and M.D. Carmichael. 2009. Effects of the dietary flavonoid quercetin upon performance and health. Current Sports Medicine Reports 8: 206–213.CrossRefPubMedGoogle Scholar
  7. Epstein, M.A., B.G. Achong, Y.M. Barr, B. Zajac, G. Henle, and W. Henle. 1966. Morphological and virological investigations on cultured Burkitt tumor lymphoblasts (strain Raji). Journal of the National Cancer Institute 37: 547–559.PubMedGoogle Scholar
  8. Felgines, C., O. Texier, C. Morand, C. Manach, A. Scalbert, F. Regerat, and C. Remesy. 2000. Bioavailability of the flavanone naringenin and its glycosides in rats. American Journal of Physiology Gastrointestinal and Liver Physiology 279: G1148–G1154.PubMedGoogle Scholar
  9. Friese, M.A., J. Wischhusen, W. Wick, M. Weiler, G. Eisele, A. Steinle, and M. Weller. 2004. RNA interference targeting transforming growth factor-beta enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. Cancer Research 64: 7596–7603.CrossRefPubMedGoogle Scholar
  10. Frydoonfar, H.R., D.R. Mcgrath, and A.D. Spigelman. 2002. Inhibition of proliferation of a colon cancer cell line by indole-3-carbinol. Colorectal Diseases 4: 205–207.CrossRefGoogle Scholar
  11. Guerra, N., Y.X. Tan, N.T. Joncker, A. Choy, F. Gallardo, N. Xiong, S. Knoblaugh, D. Cado, N.M. Greenberg, and D.H. Raulet. 2008. NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity 28: 571–580.PubMedCentralCrossRefPubMedGoogle Scholar
  12. Harmon, A.W., and Y.M. Patel. 2003. Naringenin inhibits phosphoinositide 3-kinase activity and glucose uptake in 3T3-L1 adipocytes. Biochemical and Biophysical Research Communications 305: 229–234.CrossRefPubMedGoogle Scholar
  13. Harmon, A.W., and Y.M. Patel. 2004. Naringenin inhibits glucose uptake in MCF-7 breast cancer cells: a mechanism for impaired cellular proliferation. Breast Cancer Research and Treatment 85: 103–110.CrossRefPubMedGoogle Scholar
  14. Havsteen, B. 1983. Flavonoids, a class of natural products of high pharmacological potency. Biochemical Pharmacology 32: 1141–1148.CrossRefPubMedGoogle Scholar
  15. Houchins, J.P., T. Yabe, C. Mcsherry, and F.H. Bach. 1991. DNA sequence analysis of NKG2, a family of related cDNA clones encoding type II integral membrane proteins on human natural killer cells. The Journal of Experimental Medicine 173: 1017–1020.CrossRefPubMedGoogle Scholar
  16. Karpova, M.B., J. Schoumans, I. Ernberg, J.I. Henter, M. Nordenskjold, and B. Fadeel. 2005. Raji revisited: cytogenetics of the original Burkitt’s lymphoma cell line. Leukemia 19: 159–161.PubMedGoogle Scholar
  17. Kawaii, S., Y. Tomono, E. Katase, K. Ogawa, and M. Yano. 1999. Quantitation of flavonoid constituents in citrus fruits. Journal of Agricultural and Food Chemistry 47: 3565–3571.CrossRefPubMedGoogle Scholar
  18. Maggioni, D., L. Biffi, G. Nicolini, and W. Garavello. 2014. Flavonoids in oral cancer prevention and therapy. European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation.Google Scholar
  19. Middleton Jr, E. 1998. Effect of plant flavonoids on immune and inflammatory cell function. Advances in Experimental Medicine and Biology 439: 175–182.CrossRefPubMedGoogle Scholar
  20. Middleton Jr, E., C. Kandaswami, and T.C. Theoharides. 2000. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacological Reviews 52: 673–751.PubMedGoogle Scholar
  21. Moretta, A., C. Bottino, M. Vitale, D. Pende, C. Cantoni, M.C. Mingari, R. Biassoni, and L. Moretta. 2001. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Annual Review of Immunology 19: 197–223.CrossRefPubMedGoogle Scholar
  22. Parhiz, H., A. Roohbakhsh, F. Soltani, R. Rezaee, and M. Iranshahi. 2015. Antioxidant and anti-inflammatory properties of the citrus flavonoids hesperidin and hesperetin: an updated review of their molecular mechanisms and experimental models. Phytotherapy Research 29: 323–331.CrossRefPubMedGoogle Scholar
  23. Pulvertaft, J.V. 1964. Cytology of Burkitt’s tumour (African Lymphoma). Lancet 1: 238–240.CrossRefPubMedGoogle Scholar
  24. Theofilopoulos, A.N., C.B. Wilson, and F.J. Dixon. 1976. The Raji cell radioimmune assay for detecting immune complexes in human sera. The Journal of Clinical Investigation 57: 169–182.PubMedCentralCrossRefPubMedGoogle Scholar
  25. Verhoeyen, M.E., A. Bovy, G. Collins, S. Muir, S. Robinson, C.H. De Vos, and S. Colliver. 2002. Increasing antioxidant levels in tomatoes through modification of the flavonoid biosynthetic pathway. Journal of Experimental Botany 53: 2099–2106.CrossRefPubMedGoogle Scholar
  26. Virgili, F., F. Acconcia, R. Ambra, A. Rinna, P. Totta, and M. Marino. 2004. Nutritional flavonoids modulate estrogen receptor alpha signaling. IUBMB Life 56: 145–151.CrossRefPubMedGoogle Scholar
  27. Vivier, E., E. Tomasello, M. Baratin, T. Walzer, and S. Ugolini. 2008. Functions of natural killer cells. Nature Immunology 9: 503–510.CrossRefPubMedGoogle Scholar
  28. Williams, R.J., J.P. Spencer, and C. Rice-Evans. 2004. Flavonoids: antioxidants or signalling molecules? Free Radical Biology and Medicine 36: 838–849.CrossRefPubMedGoogle Scholar
  29. Zhang, C., J. Zhang, J. Niu, Z. Zhou, and Z. Tian. 2008. Interleukin-12 improves cytotoxicity of natural killer cells via upregulated expression of NKG2D. Human Immunology 69: 490–500.CrossRefPubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2015

Authors and Affiliations

  1. 1.Department of Biology Education, College of EducationChungbuk National UniversityChungbukRepublic of Korea
  2. 2.College of PharmacyChungbuk National UniversityChungbuk-doRepublic of Korea

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