Effects of silibinin on growth and invasive properties of human ovarian carcinoma cells through suppression of heregulin/HER3 pathway

Tumour Biol. 2016 Mar;37(3):3913-23. doi: 10.1007/s13277-015-4220-6. Epub 2015 Oct 19.


Epithelial ovarian cancer (EOC) is the most fatal gynecological malignancy due to its high proliferative and invasive capacities. A heregulin (HRG)/HER3 autocrine loop increases proliferative and metastatic properties of EOC cells, suggesting that modulators of this signaling pathway may prove effective to trammel growth and motility of these cells. This study aimed to evaluate the effects of multi-tyrosine kinase inhibitor silibinin on proliferative and invasive characteristics of EOC cell lines OVCAR8 and SKOV3 through suppression of the HRG/HER3 pathway. To achieve this, the effects of silibinin on proliferation, DNA synthesis, clonogenicity, cell cycle progression, cathepsin B enzymatic activity, and migration and invasion were explored in vitro. Silibinin suppressed proliferation, DNA synthesis, and clonogenic abilities of OVCAR8 and SKOV3 cells through inhibition of the autocrine HRG/HER3 circuit. Silibinin-mediated attenuation of the HER3 signaling disabled the HER3/AKT/survivin axis and thereby, induced G1/S cell cycle arrest. Furthermore, silibinin reduced invasive potentials of the EOC cells through quelling the HRG/HER3 pathway and suppression of cathepsin B activity. Altogether, these results suggest that silibinin is a potential anti-cancer drug to inhibit proliferative and invasive characteristics of the EOC cells that exhibit an autocrine HRG/HER3 pathway.

Keywords: Epithelial ovarian cancer; Heregulin/HER3 signaling; Motility; Silibinin.

MeSH terms

  • Antioxidants / pharmacology
  • Blotting, Western
  • Carcinoma, Ovarian Epithelial
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects*
  • Cell Proliferation / genetics
  • DNA, Neoplasm / biosynthesis
  • DNA, Neoplasm / genetics
  • Female
  • G1 Phase Cell Cycle Checkpoints / drug effects
  • G1 Phase Cell Cycle Checkpoints / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism
  • Neoplasm Invasiveness
  • Neoplasms, Glandular and Epithelial / genetics
  • Neoplasms, Glandular and Epithelial / metabolism
  • Neoplasms, Glandular and Epithelial / pathology
  • Neuregulin-1 / genetics
  • Neuregulin-1 / metabolism*
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, ErbB-3 / genetics
  • Receptor, ErbB-3 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics
  • Silybin
  • Silymarin / pharmacology*
  • Survivin


  • Antioxidants
  • BIRC5 protein, human
  • DNA, Neoplasm
  • Inhibitor of Apoptosis Proteins
  • NRG1 protein, human
  • Neuregulin-1
  • Silymarin
  • Survivin
  • Silybin
  • ERBB3 protein, human
  • Receptor, ErbB-3
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt