EGFR and IGF-1R in regulation of prostate cancer cell phenotype and polarity: opposing functions and modulation by T-cadherin.
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.
*Department of Biomedicine, Laboratory for Signal Transduction, and Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland; and Hirslanden Klinik St. Anna, Luzern, Switzerland.
Kseniya
K
Maslova
*Department of Biomedicine, Laboratory for Signal Transduction, and Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland; and Hirslanden Klinik St. Anna, Luzern, Switzerland.
Emmanouil
E
Kyriakakis
*Department of Biomedicine, Laboratory for Signal Transduction, and Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland; and Hirslanden Klinik St. Anna, Luzern, Switzerland.
Dennis
D
Pfaff
*Department of Biomedicine, Laboratory for Signal Transduction, and Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland; and Hirslanden Klinik St. Anna, Luzern, Switzerland.
Audrey
A
Frachet
*Department of Biomedicine, Laboratory for Signal Transduction, and Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland; and Hirslanden Klinik St. Anna, Luzern, Switzerland.
Agne
A
Frismantiene
*Department of Biomedicine, Laboratory for Signal Transduction, and Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland; and Hirslanden Klinik St. Anna, Luzern, Switzerland.
Lukas
L
Bubendorf
*Department of Biomedicine, Laboratory for Signal Transduction, and Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland; and Hirslanden Klinik St. Anna, Luzern, Switzerland.
Christian
C
Ruiz
*Department of Biomedicine, Laboratory for Signal Transduction, and Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland; and Hirslanden Klinik St. Anna, Luzern, Switzerland.
Tatjana
T
Vlajnic
*Department of Biomedicine, Laboratory for Signal Transduction, and Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland; and Hirslanden Klinik St. Anna, Luzern, Switzerland.
Paul
P
Erne
*Department of Biomedicine, Laboratory for Signal Transduction, and Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland; and Hirslanden Klinik St. Anna, Luzern, Switzerland therese-j.resink@unibas.ch.
Thérèse J
TJ
Resink
*Department of Biomedicine, Laboratory for Signal Transduction, and Institute of Pathology, University Hospital Basel, University of Basel, Basel, Switzerland; and Hirslanden Klinik St. Anna, Luzern, Switzerland.
Maria
M
Philippova
D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D066246:ErbB Receptors / Q000378:metabolism*; D000077156:Gefitinib; D020868:Gene Silencing; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000737:chemistry; D008297:Male; D009361:Neoplasm Invasiveness; D010641:Phenotype; D010766:Phosphorylation; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011509:Proteoglycans / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry; D011799:Quinazolines / Q000737:chemistry; D017526:Receptor, IGF Type 1 / Q000378:metabolism*
D015820:Cadherins; D004338:Drug Combinations; C099972:H-cadherin; D007797:Laminin; C501177:NVP-AEW541; D011509:Proteoglycans; D011743:Pyrimidines; D011758:Pyrroles; D011799:Quinazolines; C059485:matrigel; D003094:Collagen; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D000077156:Gefitinib
NVP-AEW541; gefitinib; malignant and benign prostate epithelial cell lines