Differential Inhibition of the TGF-β Signaling Pathway in HCC Cells Using the Small Molecule Inhibitor LY2157299 and the D10 Monoclonal Antibody against TGF-β Receptor Type II

PLoS One. 2013 Jun 27;8(6):e67109. doi: 10.1371/journal.pone.0067109. Print 2013.

Abstract

We investigated blocking the TGF-β signaling pathway in HCC using two small molecule inhibitors (LY2157299, LY2109761) and a neutralizing humanized antibody (D10) against TGF-βRII. LY2157299 and LY2109761 inhibited HCC cell migration on Laminin-5, Fibronectin, Vitronectin, Fibrinogen and Collagen-I and de novo phosphorylation of pSMAD2. LY2157299 inhibited HCC migration and cell growth independently of the expression levels of TGF-βRII. In contrast to LY2157299, D10 showed a reduction in pSMAD2 only after a short exposure. This study supports the use of LY2157299 in clinical trials, and presents new insights into TGF-β receptor cycling in cancer cells.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Connective Tissue Growth Factor / metabolism
  • Female
  • Hep G2 Cells
  • Homeodomain Proteins / pharmacology*
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Male
  • Middle Aged
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Pyrazoles / pharmacology*
  • Pyrroles / pharmacology
  • Quinolines / pharmacology*
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / drug effects
  • Smad2 Protein / metabolism
  • Transcription Factors / pharmacology*
  • Transforming Growth Factor beta / metabolism
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Antineoplastic Agents
  • CCN2 protein, human
  • Homeodomain Proteins
  • LY2109761
  • Pyrazoles
  • Pyrroles
  • Quinolines
  • Receptors, Transforming Growth Factor beta
  • SMAD2 protein, human
  • Smad2 Protein
  • Transcription Factors
  • Transforming Growth Factor beta
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Connective Tissue Growth Factor
  • HOXD10 protein, human
  • LY-2157299
  • Protein Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II

Grants and funding

This work was supported by the Italian Association of Cancer Research (AIRC) (grant number IG11389 to G.G.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.