Prostate cancer: A model of integration of genomic and non-genomic effects of the androgen receptor in cell lines model

• Published in: Steroids 2008-10, Vol.73 (9), p.1030-1037
• Main Authors: Bonaccorsi, Lorella, Nosi, Daniele, Quercioli, Franco, Formigli, Lucia, Zecchi, Sandra, Maggi, Mario, Forti, Gianni, Baldi, Elisabetta
• Format: Article
• Language: English
• Subjects: Androgen receptor; Animals; Biological and medical sciences; Cell Line, Tumor; Cell Membrane - metabolism; Cholesterol - metabolism; Fundamental and applied biological sciences. Psychology; Genome; Gynecology. Andrology. Obstetrics; Humans; Lipid rafts; Lysosomes - metabolism; Male; Male genital diseases; Medical sciences; Membrane Microdomains; Models, Biological; Nephrology. Urinary tract diseases; Phenotype; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptor, Epidermal Growth Factor - metabolism; Receptors, Androgen - metabolism; Signal Transduction; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Vertebrates: endocrinology
• ISSN: 0039-128X; 1878-5867
• DOI: 10.1016/j.steroids.2008.01.028

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.