Silibinin inhibits UVB- and epidermal growth factor-induced mitogenic and cell survival signaling involving activator protein-1 and nuclear factor-kappaB in mouse epidermal JB6 cells

Mol Cancer Ther. 2006 May;5(5):1145-53. doi: 10.1158/1535-7163.MCT-05-0478.


UVB radiation is the major etiologic factor in the development of nonmelanoma skin cancer. In addition to tumor-initiating effect, UVB also causes tumor promotion via mitogenic and survival signaling. Studies have shown strong preventive effects of silibinin against both UVB-induced and chemically induced tumor promotion in mouse skin models; however, mechanisms are not understood completely. Here, we used tumor promoter-sensitive JB6 mouse epithelial cell model and studied the effect of silibinin on two different mitogens [UVB and epidermal growth factor (EGF)] that induce mitogenic and cell survival signaling pathways. UVB (50-800 mJ/cm(2)) dose-dependently induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun-NH(2)-kinase 1/2 (JNK1/2), and p38 kinase (p38K) as well as Akt, with an optimum response at 400 mJ/cm(2) UVB dose. UVB caused a biphasic phosphorylation of ERK1/2 in a time kinetics study. Silibinin treatment before or immediately after UVB exposure, or both, resulted in a strong decrease in UVB-caused phosphorylation of ERK1/2 and Akt in both dose- and time-dependent manner, without any substantial response on JNK1/2 and p38K. Silibinin also suppressed UVB-induced activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) activation, which are activated by ERK1/2 and Akt. Silibinin treatment under similar conditions also strongly inhibited EGF-induced ERK1/2, JNK1/2, and p38K as well as Akt phosphorylation, and also suppressed EGF-induced AP-1 and NF-kappaB activation. Because AP-1 and NF-kappaB are important nuclear transcription factors for tumor promotion, these results suggest that silibinin possibly prevents skin tumor promotion by inhibiting UVB- and EGF-induced mitogenic and cell survival signaling involving both AP-1 and NF-kappaB.

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Antioxidants / pharmacology*
  • Cell Survival* / drug effects
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • Epidermal Cells
  • Epidermal Growth Factor / pharmacology*
  • Epidermis / drug effects
  • Epidermis / metabolism*
  • Keratinocytes / metabolism
  • MAP Kinase Signaling System / radiation effects
  • Mice
  • Mitosis / drug effects
  • Mitosis / radiation effects
  • Models, Biological
  • NF-kappa B / metabolism*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / radiation effects
  • Silybin
  • Silymarin / metabolism
  • Silymarin / pharmacology
  • Transcription Factor AP-1 / metabolism*
  • Ultraviolet Rays* / adverse effects


  • Antioxidants
  • NF-kappa B
  • Silymarin
  • Transcription Factor AP-1
  • Silybin
  • Epidermal Growth Factor
  • Proto-Oncogene Proteins c-akt