Berberine induces FasL-related apoptosis through p38 activation in KB human oral cancer cells

Oncol Rep. 2015 Apr;33(4):1775-82. doi: 10.3892/or.2015.3768. Epub 2015 Jan 29.


In the present study, we examined the anticancer properties of berberine in KB oral cancer cells with a specific focus on its cellular mechanism. Berberine did not affect the cell viability of the primary human normal oral keratinocytes that were used as a control. However, the viability of KB cells was found to decrease significantly in the presence of berberine in a dose-dependent manner. Furthermore, in KB cells, berberine induced the fragmentation of genomic DNA, changes in cell morphology, and nuclear condensation. In addition, caspase-3 and -7 activation, and an increase in apoptosis were observed. Berberine was also found to upregulate significantly the expression of the death receptor ligand, FasL. In turn, this upregulation triggered the activation of pro-apoptotic factors such as caspase-8, -9 and -3 and poly(ADP-ribose) polymerase (PARP). Furthermore, pro-apoptotic factors such as Bax, Bad and Apaf-1 were also significantly upregulated by berberine. Anti-apoptotic factors such as Bcl-2 and Bcl-xL were downregulated. Z-VAD-FMK, a cell-permeable pan-caspase inhibitor, suppressed the activation of caspase-3 and PARP. These results clearly indicate that berberine-induced cell death of KB oral cancer cells was mediated by both extrinsic death receptor-dependent and intrinsic mitochondrial-dependent apoptotic signaling pathways. In addition, berberine-induced upregulation of FasL was shown to be mediated by the p38 MAPK signaling pathway. We also found that berberine-induced migration suppression was mediated by downregulation of MMP-2 and MMP-9 through phosphorylation of p38 MAPK. In summary, berberine has the potential to be used as a chemotherapeutic agent, with limited side-effects, for the management of oral cancer.

MeSH terms

  • Apoptosis / drug effects*
  • Apoptotic Protease-Activating Factor 1 / metabolism
  • Berberine / therapeutic use*
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Fas Ligand Protein / metabolism*
  • Flow Cytometry
  • Humans
  • Immunoblotting
  • Mouth Neoplasms / drug therapy*
  • Mouth Neoplasms / enzymology
  • Mouth Neoplasms / pathology
  • bcl-2-Associated X Protein / metabolism
  • bcl-Associated Death Protein / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • APAF1 protein, human
  • Apoptotic Protease-Activating Factor 1
  • BAD protein, human
  • BAX protein, human
  • FASLG protein, human
  • Fas Ligand Protein
  • bcl-2-Associated X Protein
  • bcl-Associated Death Protein
  • Berberine
  • p38 Mitogen-Activated Protein Kinases
  • Caspase 3
  • Caspase 7