Prostate cancer: a model of integration of genomic and non-genomic effects of the androgen receptor in cell lines model.
Androgens and the androgen receptor (AR) are involved both in early tumorigenesis of prostate cancer (PCa) and in androgen-refractory disease. The role of AR signalling has also been highlighted by the fusion gene TMPRSS2:ERG recently identified in the majority of PCa. Several data indicate that re-expression of AR in PCa cell lines confers a less aggressive phenotype. We observed that re-expression of AR in the AR-negative cells PC3 decreases anchorage-independent growth and Matrigel invasiveness of PC3-AR cells where plasma membrane interaction between AR and EGFR led to an interference with downstream signalling and internalization of activated EGFR. Our data evidenced a shift of EGFR internalization pathway from the clathrin-coated pit one mediating signalling and recycling of EGFR to the lipid raft-mediated one mainly involved in lysosomal degradation of EGFR. These effects involved an altered recruitment to EGFR of the adaptor proteins Grb2 and c-Cbl followed by a reduced ubiquitination of EGFR. Our preliminary results suggest that in PC3-AR cells a pool of classical AR is located within cholesterol-rich membrane microdomains (namely as lipid rafts) and a population of EGFR is within cholesterol-rich membrane microdomains too. However, AR and EGFR membrane interaction that is increased by rapid androgen signalling is not within cholesterol-rich membrane microdomains. Our data enlighten that the crosstalk between genotropic and non-genotropic AR signalling interferes with signalling of EGFR in response to ligand leading to a lower invasive phenotype of AR-positive PCa cells.
Bonaccorsi
Lorella
L
Department of Clinical Physiopathology, Andrology Unit, Viale Pieraccini 6, I-50139 Florence, Italy. l.bonaccorsi@dfc.unifi.it
Nosi
Daniele
D
Quercioli
Franco
F
Formigli
Lucia
L
Zecchi
Sandra
S
Maggi
Mario
M
Forti
Gianni
G
Baldi
Elisabetta
E
D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D016678:Genome; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D021962:Membrane Microdomains; D008954:Models, Biological; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction
D011944:Receptors, Androgen; D002784:Cholesterol; D066246:ErbB Receptors