Long-term presence of androgens and anti-androgens modulate EGF-receptor expression and MAP-kinase phosphorylation in androgen receptor-prostate positive cancer cells.
Prostate cancer (Pca) progression from an androgen-dependent to an androgen-independent state occurs in patients who undergo hormonal therapy. There is evidence indicating that deregulation of the epidermal growth factor receptor (EGFR) pathway plays a critical role in this phenomenon. In this study we addressed the question by stably transfecting the androgen receptor (AR) cDNA into the AR-negative Pca cell line DU145 that expresses high levels of EGFR. The resulting cell line has been named DU145-AR. We showed that the introduction of the AR restored positive androgen regulation of tumour cell growth and gene expression in vitro. The DU145-AR cells grown in culture medium containing androgens exhibited a transient up-regulation of EGFR levels with a subsequent down-regulation. This phenomenon was reversible, upon addition of hydroxiflutamide (HF) to the culture medium, but after prolonged treatment. When the EGFR repression is relieved in the presence of HF, the cells become more responsive either to EGF mediated growth or to anti-proliferative effect of PKI166, an inhibitor of EGFR phosphorylation. Moreover, we found a significant increase of the activated form of mitogen-activated-protein kinase (MAPK) in cells treated with HF. PKI166 blocked this HF mediated-MAPK activation, suggesting that the activation of MAPK is an event dependent on EGFR function. Our data demonstrate that hormone sensitive Pca cells possess a mechanism able to limit EGFR expression. Up-regulation of EGFR in response to long-term HF treatment could represent an attempt to rescue cell growth through a compensatory survival pathway.
Gravina
Giovanni Luca
GL
Division of Urology, Department of Surgery, University of L'Aquila, L'Aquila, Italy.
Festuccia
Claudio
C
Angelucci
Adriano
A
Poletti
Angelo
A
Capuano
Daila
D
Vicentini
Carlo
C
Motta
Marcella
M
Bologna
Mauro
M
D000726:Androgen Antagonists / Q000494:pharmacology*; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011944:Receptors, Androgen / Q000032:analysis; D015854:Up-Regulation / Q000187:drug effects*
D000726:Androgen Antagonists; D000728:Androgens; D011944:Receptors, Androgen; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases