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.
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Havsteen, B. 1983. Flavonoids, a class of natural products of high pharmacological potency. Biochemical Pharmacology 32: 1141–1148.
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.
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.
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.
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.
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.
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.
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.
Pulvertaft, J.V. 1964. Cytology of Burkitt’s tumour (African Lymphoma). Lancet 1: 238–240.
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.
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.
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.
Vivier, E., E. Tomasello, M. Baratin, T. Walzer, and S. Ugolini. 2008. Functions of natural killer cells. Nature Immunology 9: 503–510.
Williams, R.J., J.P. Spencer, and C. Rice-Evans. 2004. Flavonoids: antioxidants or signalling molecules? Free Radical Biology and Medicine 36: 838–849.
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.
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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
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DOI: https://doi.org/10.1007/s12272-015-0624-5