EGFR and IGF-1R in regulation of prostate cancer cell phenotype and polarity: opposing functions and modulation by T-cadherin

FASEB J. 2015 Feb;29(2):494-507. doi: 10.1096/fj.14-249367. Epub 2014 Nov 7.


T-cadherin is an atypical glycosylphosphatidylinsoitol-anchored member of the cadherin superfamily of adhesion molecules. We found that T-cadherin overexpression in malignant (DU145) and benign (BPH-1) prostatic epithelial cell lines or silencing in the BPH-1 cell line, respectively, promoted or inhibited migration and spheroid invasion in collagen I gel and Matrigel. T-cadherin-dependent effects were associated with changes in cell phenotype: overexpression caused cell dissemination and loss of polarity evaluated by relative positioning of the Golgi/nuclei in cell groups, whereas silencing caused formation of compact polarized epithelial-like clusters. Epidermal growth factor receptor (EGFR) and IGF factor-1 receptor (IGF-1R) were identified as mediators of T-cadherin effects. These receptors per se had opposing influences on cell phenotype. EGFR activation with EGF or IGF-1R inhibition with NVP-AEW541 promoted dissemination, invasion, and polarity loss. Conversely, inhibition of EGFR with gefitinib or activation of IGF-1R with IGF-1 rescued epithelial morphology and decreased invasion. T-cadherin silencing enhanced both EGFR and IGF-1R phosphorylation, yet converted cells to the morphology typical for activated IGF-1R. T-cadherin effects were sensitive to modulation of EGFR or IGF-1R activity, suggesting direct involvement of both receptors. We conclude that T-cadherin regulates prostate cancer cell behavior by tuning the balance in EGFR/IGF-1R activity and enhancing the impact of IGF-1R.

Keywords: NVP-AEW541; gefitinib; malignant and benign prostate epithelial cell lines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cadherins / metabolism*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Nucleus / metabolism
  • Cell Survival
  • Collagen / chemistry
  • Drug Combinations
  • ErbB Receptors / metabolism*
  • Gefitinib
  • Gene Silencing
  • Golgi Apparatus / metabolism
  • Humans
  • Laminin / chemistry
  • Male
  • Neoplasm Invasiveness
  • Phenotype
  • Phosphorylation
  • Prostate / metabolism*
  • Prostatic Neoplasms / metabolism*
  • Proteoglycans / chemistry
  • Pyrimidines / chemistry
  • Pyrroles / chemistry
  • Quinazolines / chemistry
  • Receptor, IGF Type 1 / metabolism*


  • Cadherins
  • Drug Combinations
  • H-cadherin
  • Laminin
  • NVP-AEW541
  • Proteoglycans
  • Pyrimidines
  • Pyrroles
  • Quinazolines
  • matrigel
  • Collagen
  • ErbB Receptors
  • Receptor, IGF Type 1
  • Gefitinib