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

J Microbiol Biotechnol. 2022 Apr 28;32(4):397-404. doi: 10.4014/jmb.2201.01010.


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: Apigenin; CD95L(FasL;CD178); HCC; HIF-1α; NK.

MeSH terms

  • Apigenin / metabolism
  • Apigenin / pharmacology
  • Carcinoma, Hepatocellular* / pathology
  • Cell Line, Tumor
  • Fas Ligand Protein / metabolism
  • Humans
  • Killer Cells, Natural
  • Liver Neoplasms* / pathology
  • fas Receptor / metabolism*


  • FAS protein, human
  • Fas Ligand Protein
  • fas Receptor
  • Apigenin