The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells.
Many recent evidences indicate that androgen-sensitive prostate cancer cells have a lower malignant phenotype that is in particular characterized by a reduced migration and invasion. We previously demonstrated that expression of androgen receptor (AR) by transfection of the androgen-independent prostate cancer cell line PC3 decreases invasion and adhesion of these cells (PC3-AR) through modulation of alpha6beta4 integrin expression. The treatment with the synthetic androgen R1881 further reduced invasion of the cells without, however, modifying alpha6beta4 expression on the cell surface, suggesting an interference with the invasion process in response to EGF. We investigated whether the presence of the AR could affect EGF receptor (EGFR)-mediated signaling in response to EGF by evaluating autotransphosphorylation of the receptor as well as activation of downstream signalling pathways. Immunoprecipitation studies demonstrated a reduction of EGF-induced tyrosine phosphorylation of EGFR in PC3-AR cells. In addition, EGF-stimulated PI3K activity, a key signalling pathway for invasion of these cells, was decreased in PC3-AR cells and further reduced by treatment with R1881, indicating decreased functionality of EGFR. An interaction between EGFR and AR has been demonstrated by immunoconfocal and co-immunoprecipitation analysis in PC3-AR cells, suggesting a possible interference of AR on EGFR signalling by interaction of the two proteins. In conclusion, our results suggest that the expression of AR by transfection in PC3 cells confers a less malignant phenotype by interfering with EGFR autophosphorylation and signalling in response to EGF leading to invasion through a mechanism involving an interaction between AR and EGFR.
Bonaccorsi
L
L
Dipartimenti di Fisiopatologia Clinica (Unità di Andrologia), Univerisity of Florence, Florence, Italy. l.bonaccorsi@dfc.unifi.it
Muratori
M
M
Carloni
V
V
Marchiani
S
S
Formigli
L
L
Forti
G
G
Baldi
E
E
D000728:Androgens / Q000494:pharmacology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D039161:Integrin alpha6beta4 / Q000096:biosynthesis; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000728:Androgens; D039161:Integrin alpha6beta4; D011944:Receptors, Androgen; D015741:Metribolone; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors