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- Title
EGFR and IGF-1R in regulation of prostate cancer cell phenotype and polarity: opposing functions and modulation by T-cadherin.
- Authors
Maslova, Kseniya; Kyriakakis, Emmanouil; Pfaff, Dennis; Frachet, Audrey; Frismantiene, Agne; Bubendorf, Lukas; Ruiz, Christian; Vlajnic, Tatjana; Erne, Paul; Resink, Thérèse J.; Philippova, Maria
- Abstract
T-cadherin is an atypical glycosylphosphati-dylinsoitol-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.
- Subjects
EPITHELIAL cells; CANCER cells; CADHERINS; CELL adhesion molecules; GEFITINIB; PROSTATE cancer
- Publication
FASEB Journal, 2015, Vol 29, Issue 2, p494
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.14-249367