Silibinin induces apoptosis through inhibition of the mTOR-GLI1-BCL2 pathway in renal cell carcinoma

Oncol Rep. 2015 Nov;34(5):2461-8. doi: 10.3892/or.2015.4224. Epub 2015 Aug 26.


The downstream transcriptional factor of the hedgehog (Hh) pathway, GLI family zinc finger 1 (GLI1), plays a crucial role in regulating tumor progression. In the present study, we demonstrated that silibinin, a natural flavonoid antioxidant isolated from extracts of the milk thistle herb, exerts its anticancer capabilities by restraining GLI1 function in renal cell carcinoma (RCC) cells in vitro and in vivo. In the present study, we confirmed that silibinin induced growth inhibition of RCC through caspase-dependent apoptosis and downregulation of GLI1 and BCL2, which could be partially reversed by GLI1 overexpression. Moreover, we determined that the decreased GLI1 expression by silibinin was mediated by the mammalian target of rapamycin (mTOR) pathway. The in vivo mouse xenograft study also showed that silibinin significantly reduced RCC tumor growth and specifically targeted the mTOR-GLI1-BCL2 signaling pathway. In conclusion, our findings demonstrated for the first time that silibinin induces apoptosis of RCC cells through inhibition of the mTOR-GLI1‑BCL2 pathway. These findings also indicate that GLI1 is a novel regulator for the potential therapeutic application of silibinin against RCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects*
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / pathology
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / pathology
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Signal Transduction
  • Silybin
  • Silymarin / pharmacology*
  • Silymarin / therapeutic use
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / metabolism
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays
  • Zinc Finger Protein GLI1


  • Antineoplastic Agents
  • BCL2 protein, human
  • GLI1 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • Silymarin
  • Transcription Factors
  • Zinc Finger Protein GLI1
  • Silybin
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • CASP3 protein, human
  • Caspase 3