Journal of Microbiology and Biotechnology

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
권호 표지
DOI QR코드

DOI QR Code

Apigenin Increases Natural Killer Cytotoxicity to Human Hepatocellular Carcinoma Expressing HIF-1α through High Interaction of CD95/CD95L

  • Lee, Hwan Hee (Department of Pharmacy, Duksung Women's University) ;
  • Cho, Hyosun (Department of Pharmacy, Duksung Women's University)
  • Received : 2022.01.11
  • Accepted : 2022.02.25
  • Published : 2022.04.28
Download PDF
⟨ Previous Next ⟩

Abstract

Natural killer (NK) cell activity is more attenuated in hepatocellular carcinoma (HCC) patients than normal. Hypoxic-inducible factor (HIF)-1α is highly expressed in tumors to maintain their metabolism in a hypoxic environment. The expression of HIF-1α in cancers can lead to cell growth, proliferation, invasion/metastasis and immune escape. Although apigenin, a flavonoid, is known to have various biological activities, it has not been demonstrated in NK cell immune activity in HCC cells. In this study, NK-92 cells were directly cocultured with HCC SK-Hep1 cells for 24 h to evaluate NK cell activity in HCC cells or HCC cells expressing HIF-1α by apigenin. NK cell cytotoxicity to HCC cells expressing HIF-1α was significantly increased, and NK cell-activating receptors, NKG2D, NKp30 and NKp44 were highly expressed. The activating effect of apigenin on NK cells substantially induced apoptosis in HCC cells expressing HIF-1α through high expression of CD95L on the surface of NK-92 cells. Moreover, apigenin excellently inhibited the level of TGF-β1 in a coculture of NK cells and HCC cells. In conclusion, apigenin seems to be a good compound that increases NK cell cytotoxicity to HCC cells by controlling HIF-1α expression.

Keywords

Acknowledgement

This work was supported by the Priority Research Center Program through the NRF funded by the Korean Ministry of Education, Science and Technology (2016R1A6A1A03007648) and was also funded by the Basic Science Research Program of the National Research Foundation of Korea (NRF) (NRF- 2020R1I1A1A01074412).

References

  1. El-Serag HB. 2011. Hepatocellular carcinoma. N. Engl. J. Med. 365: 1118-1127. https://doi.org/10.1056/NEJMra1001683
  2. Marengo A, Rosso C, Bugianesi E. 2016. Liver cancer: Connections with obesity, fatty liver, and cirrhosis. Annu. Rev. Med. 67: 103-117. https://doi.org/10.1146/annurev-med-090514-013832
  3. Khemlina G, Ikeda S, Kurzrock R. 2017. The biology of Hepatocellular carcinoma: implications for genomic and immune therapies. Mol. Cancer 16: 149. https://doi.org/10.1186/s12943-017-0712-x
  4. Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. 2015. Genetic landscape and biomarkers of Hepatocellular Carcinoma. Gastroenterology 149: 1226-1239. e1224. https://doi.org/10.1053/j.gastro.2015.05.061
  5. Helmlinger G, Yuan F, Dellian M, Jain RK. 1997. Interstitial pH and pO2 gradients in solid tumors in vivo: High-resolution measurements reveal a lack of correlation. Nat. Med. 3: 177-182. https://doi.org/10.1038/nm0297-177
  6. Patrick H Maxwell CWP, Peter J Ratcliffe. 2001. Activation of the HIF pathway in cancer. Curr. Opin. Genet. Dev. 11: 293-299. https://doi.org/10.1016/S0959-437X(00)00193-3
  7. Brahimi-Horn MC, Pouyssegur J. 2007. Oxygen, a source of life and stress. FEBS Lett. 581: 3582-3591. https://doi.org/10.1016/j.febslet.2007.06.018
  8. Multhoff G, Vaupel P. 2020. Hypoxia Compromises anti-cancer immune responses. Adv. Exp. Med. Biol. 1232: 131-143. https://doi.org/10.1007/978-3-030-34461-0_18
  9. Voskoboinik I, Whisstock JC, Trapani JA. 2015. Perforin and granzymes: function, dysfunction and human pathology. Nat. Rev. Immunol. 15: 388-400. https://doi.org/10.1038/nri3839
  10. Stiglund N, Strand K, Cornillet M, Stal P, Thorell A, Zimmer CL, et al. 2019. Retained NK cell phenotype and functionality in nonalcoholic fatty liver disease. Front. Immunol. 10: 1255. https://doi.org/10.3389/fimmu.2019.01255
  11. Cai L, Zhang Z, Zhou L, Wang H, Fu J, Zhang S, et al. 2008. Functional impairment in circulating and intrahepatic NK cells and relative mechanism in hepatocellular carcinoma patients. Clin. Immunol. 129: 428-437. https://doi.org/10.1016/j.clim.2008.08.012
  12. Prager I, Liesche C, van Ooijen H, Urlaub D, Verron Q, Sandstrom N, et al. 2019. NK cells switch from granzyme B to death receptor-mediated cytotoxicity during serial killing. J. Exp. Med. 216: 2113-2127. https://doi.org/10.1084/jem.20181454
  13. Barrow AD, Martin CJ, Colonna M. 2019. The natural cytotoxicity receptors in health and disease. Front. Immunol. 10: 909. https://doi.org/10.3389/fimmu.2019.00909
  14. Peter ME, Krammer PH. 2003. The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ. 10: 26-35. https://doi.org/10.1038/sj.cdd.4401186
  15. Zsofia Edit Papay AK, Bela Boddi, Zahra Merchant, Imran Y Saleem, Mohammed Gulrez Zariwala, Imre Klebovich, et al. 2017. Study on the pulmonary delivery system of apigenin-loaded albumin nanocarriers with antioxidant activity. J. Aerosol Med. Pulm. Drug Deliv. 30: 274-288. https://doi.org/10.1089/jamp.2016.1316
  16. Yuan-Chuen Wang K-MH. 2013. In vitro anti-inflammatory effect of apigenin in the Helicobacter pylori-infected gastric adenocarcinoma cells. Food Chem. Toxicol. 53: 376-383. https://doi.org/10.1016/j.fct.2012.12.018
  17. Berrin Ozcelik MK, Ilkay Orhan. 2009. Cytotoxicity, antiviral and antimicrobial activities of alkaloids, flavonoids, and phenolic acids. Pharm. Biol. 49: 396-402. https://doi.org/10.3109/13880209.2010.519390
  18. Yan X, Qi M, Li P, Zhan Y, Shao H. 2017. Apigenin in cancer therapy: anti-cancer effects and mechanisms of action. Cell Biosci. 7: 50. https://doi.org/10.1186/s13578-017-0179-x
  19. Zhang W, Qiao H, Lv Y, Wang J, Chen X, Hou Y, et al. 2014. Apigenin inhibits enterovirus-71 infection by disrupting viral RNA association with trans-acting factors. PLoS One 9: e110429. https://doi.org/10.1371/journal.pone.0110429
  20. Aung MOMH, Mat Nor N, Mohd Adnan LH, Ahmad NZ, Septama AW, Nik Nurul Najihah NNN, et al. 2021. Effects of apigenin, luteolin, and quercetin on the Natural Killer (NK-92) cells proliferation: A potential role as immunomodulator. Sains Malaysiana 50: 821-828. https://doi.org/10.17576/jsm-2021-5003-22
  21. Oshimi Y, Oda S, Honda Y, Nagata S, Miyazaki S. 1996. Involvement of Fas ligand and Fas-mediated pathway in the cytotoxicity of human natural killer cells. J. Immunol. 157: 2909-2915.
  22. Suda T, Takahashi T, Golstein P, Nagata S. 1993. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75: 1169-1178. https://doi.org/10.1016/0092-8674(93)90326-l
  23. Viel S, Marcais A, Guimaraes FS, Loftus R, Rabilloud J, Grau M, et al. 2016. TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci. Signal. 9: ra19. https://doi.org/10.1126/scisignal.aad1884
  24. Sung PS, Jang JW. 2018. Natural killer cell dysfunction in hepatocellular carcinoma: pathogenesis and clinical implications. Int. J. Mol. Sci. 19: 3648. https://doi.org/10.3390/ijms19113648
  25. Vaupel P, Harrison L. 2004. Tumor hypoxia: causative factors, compensatory mechanisms, and cellular response. Oncologist 9 Suppl 5: 4-9. https://doi.org/10.1634/theoncologist.9-90005-4
  26. Erler JT, Cawthorne CJ, Williams KJ, Koritzinsky M, Wouters BG, Wilson C, et al. 2004. Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and -independent mechanisms and contributes to drug resistance. Mol. Cell. Biol. 24: 2875-2889. https://doi.org/10.1128/MCB.24.7.2875-2889.2004
  27. Peng XH, Karna P, Cao Z, Jiang BH, Zhou M, Yang L. 2006. Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J. Biol. Chem. 281: 25903-25914. https://doi.org/10.1074/jbc.M603414200
  28. Tao L, Huang G, Song H, Chen Y, Chen L. 2017. Cancer associated fibroblasts: an essential role in the tumor microenvironment. Oncol. Lett. 14: 2611-2620. https://doi.org/10.3892/ol.2017.6497
  29. Trapani JA, Davis J, Sutton VR, Smyth MJ. 2000. Proapoptotic functions of cytotoxic lymphocyte granule constituents in vitro and in vivo. Curr. Opin. Immunol. 12: 323-329. https://doi.org/10.1016/S0952-7915(00)00094-7
  30. Yadav A, Kumar B, Datta J, Teknos TN, Kumar P. 2011. IL-6 promotes head and neck tumor metastasis by inducing epithelial-mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Mol. Cancer Res. 9: 1658-1667. https://doi.org/10.1158/1541-7786.MCR-11-0271
  31. Braun DA, Fribourg M, Sealfon SC. 2013. Cytokine response is determined by duration of receptor and signal transducers and activators of transcription 3 (STAT3) activation. J. Biol. Chem. 288: 2986-2993. https://doi.org/10.1074/jbc.M112.386573
  32. Gao Y, Souza-Fonseca-Guimaraes F, Bald T, Ng SS, Young A, Ngiow SF, et al. 2017. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat. Immunol. 18: 1004-1015. https://doi.org/10.1038/ni.3800
  33. Palomares O, Martin-Fontecha M, Lauener R, Traidl-Hoffmann C, Cavkaytar O, Akdis M, et al. 2014. Regulatory T cells and immune regulation of allergic diseases: roles of IL-10 and TGF-β. Genes Immun. 15: 511-520. https://doi.org/10.1038/gene.2014.45
  34. Jelicic K, Cimbro R, Nawaz F, Huang da W, Zheng X, Yang J, et al. 2013. The HIV-1 envelope protein gp120 impairs B cell proliferation by inducing TGF-β1 production and FcRL4 expression. Nat. Immunol. 14: 1256-1265. https://doi.org/10.1038/ni.2746
  35. Andrianifahanana M, Singh AP, Nemos C, Ponnusamy MP, Moniaux N, Mehta PP, et al. 2007. IFN-gamma-induced expression of MUC4 in pancreatic cancer cells is mediated by STAT-1 upregulation: a novel mechanism for IFN-gamma response. Oncogene 26: 7251-7261. https://doi.org/10.1038/sj.onc.1210532
  36. Chapela PJ, Broaddus RR, Hawkins SM, Lessey BA, Carson DD. 2015. Cytokine stimulation of MUC4 expression in human female reproductive tissue carcinoma cell lines and endometrial cancer. J .Cell Biochem. 116: 2649-2657. https://doi.org/10.1002/jcb.25213
  37. Singh AP, Moniaux N, Chauhan SC, Meza JL, Batra SK. 2004. Inhibition of MUC4 expression suppresses pancreatic tumor cell growth and metastasis. Cancer Res. 64: 622-630. https://doi.org/10.1158/0008-5472.CAN-03-2636
  38. Singh S, Kumar S, Srivastava RK, Nandi A, Thacker G, Murali H, et al. 2020. Loss of ELF5-FBXW7 stabilizes IFNGR1 to promote the growth and metastasis of triple-negative breast cancer through interferon-γ signalling. Nat. Cell Biol. 22: 591-602. https://doi.org/10.1038/s41556-020-0495-y
  39. Lee HH, Kim D, Jung J, Kang H, Cho H. 2021. NLRP3 deficiency in hepatocellular carcinoma enhances surveillance of NK-92 through a modulation of MICA/B. Int. J. Mol. Sci. 22: 9285. https://doi.org/10.3390/ijms22179285
  40. Hu XY, Liang JY, Guo XJ, Liu L, Guo YB. 2015. 5-Fluorouracil combined with apigenin enhances anticancer activity through mitochondrial membrane potential (ΔΨm)-mediated apoptosis in hepatocellular carcinoma. Clin. Exp. Pharmacol. Pysiol. 42: 146-153. https://doi.org/10.1111/1440-1681.12333
  41. Kilani-Jaziri S, Mustapha N, Mokdad-Bzeouich I, El Gueder D, Ghedira K, Ghedira-Chekir L. 2016. Flavones induce immunomodulatory and anti-inflammatory effects by activating cellular anti-oxidant activity: a structure-activity relationship study. Tumour Biol. 37: 6571-6579. https://doi.org/10.1007/s13277-015-4541-5
  42. Fang J, Zhou Q, Liu LZ, Xia C, Hu X, Shi X, et al. 2007. Apigenin inhibits tumor angiogenesis through decreasing HIF-1alpha and VEGF expression. Carcinogenesis 28: 858-864. https://doi.org/10.1093/carcin/bgl205
  43. Lee YH, Bae HC, Noh KH, Song KH, Ye SK, Mao CP, et al. 2015. Gain of HIF-1α under normoxia in cancer mediates immune adaptation through the AKT/ERK and VEGFA axes. Clin. Cancer Res. 21: 1438-1446.
  44. Ou ZL, Luo Z, Wei W, Liang S, Gao TL, Lu YB. 2019. Hypoxia-induced shedding of MICA and HIF1A-mediated immune escape of pancreatic cancer cells from NK cells: role of circ_0000977/miR-153 axis. RNA Biol. 16: 1592-1603. https://doi.org/10.1080/15476286.2019.1649585
  45. Melstrom LG, Salabat MR, Ding X-Z, Strouch MJ, Grippo PJ, Mirzoeva S, et al. 2011. Apigenin down-regulates theh hypoxia response genes: HIF-1α, GLUT-1, and VEGF in human pancreatic cancer cells. J. Surg. Res. 167: 173-181. https://doi.org/10.1016/j.jss.2010.10.041