Skip to main content
Log in

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

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

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.

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

Access this article

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

Instant access to the full article PDF.

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

Similar content being viewed by others

References

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  Google Scholar 

  • 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Havsteen, B. 1983. Flavonoids, a class of natural products of high pharmacological potency. Biochemical Pharmacology 32: 1141–1148.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

  • Middleton Jr, E. 1998. Effect of plant flavonoids on immune and inflammatory cell function. Advances in Experimental Medicine and Biology 439: 175–182.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Pulvertaft, J.V. 1964. Cytology of Burkitt’s tumour (African Lymphoma). Lancet 1: 238–240.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

  • Vivier, E., E. Tomasello, M. Baratin, T. Walzer, and S. Ugolini. 2008. Functions of natural killer cells. Nature Immunology 9: 503–510.

    Article  CAS  PubMed  Google Scholar 

  • Williams, R.J., J.P. Spencer, and C. Rice-Evans. 2004. Flavonoids: antioxidants or signalling molecules? Free Radical Biology and Medicine 36: 838–849.

    Article  CAS  PubMed  Google Scholar 

  • 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.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jae Kwon Lee.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, J.H., Lee, J.K. Naringenin enhances NK cell lysis activity by increasing the expression of NKG2D ligands on Burkitt’s lymphoma cells. Arch. Pharm. Res. 38, 2042–2048 (2015). https://doi.org/10.1007/s12272-015-0624-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-015-0624-5

Keywords

Navigation