Androgen Receptor: Joy and Pain of Castration Resistant Prostate Cancer

Background: Prostate cancer (PCa) is the most frequently diagnosed cancer among men and the second leading cause of cancer-related deaths in Western countries. The first-line treatment is androgen deprivation therapy (ADT) but, unfortunately, most patients with advanced disease develop drug-resistance and eventually progress to Castration Resistant Prostate Cancer (CRPC), for which there are no efficient therapies. Despite hormone independence, high androgen receptor (AR) levels are expressed in CRPC, indicating that the receptor still plays a role in tumor survival and progression, possibly through crosstalk with survival and metastatic pathways. The aim of this research is to investigate the role of AR signaling in modulating the mitogenic response elicited by EGF in androgen-independent PC-derived cells. Methods: Using androgen-independent, AR-expressing C4-2B prostate cancer cells, we combined several approaches such as Colony Assay, BrdU incorporation assay, Co-Ip and Western Blot analysis, Immunofluorescence approaches to study the interaction between AR signaling and EGF response. Results: AR signaling inhibits the mitogenic response induced by EGF while leaving the growth factor’s effect on cell motility and invasiveness unaltered. This is likely caused by delayed degradation of EGFR and deregulation of the ACK1/Clathrin HC internalization complex, resulting in a high EGFR protein level and a extended EGFR signaling. Additionally, ERK activation is stronger and more prolonged in cells treated with EGF plus R1881, while the cyclin/cdk inhibitor p27 is retained in the nucleus, leading to reduced cell proliferation. The AR antagonist Bicalutamide reverses the R1881-induced inhibition of EGF-stimulated proliferation, confirming the involvement of the receptor. Conclusions: Androgens delay EGF-induced EGFR downregulation, thereby modifying and prolonging EGFR-dependent signaling in metastatic CRPC cells. These findings highlight an opposite role of AR in CRPC cells compared to hormone-sensitive prostate cancer cells. Understanding the mechanisms underlying this effect on cell proliferation could lead to new anti-cancer therapies for CRPC and support the use of intermittent androgen deprivation (IAD) therapy, improving patient’s quality of life.