Analysis of Androgen Receptor Rapid Actions in Cellular Signaling Pathways: Receptor/Src Association

Much evidence indicates that, with few exceptions, non-genomic actions of steroids are mediated by receptors universally known as nuclear receptors. Steroid receptors do not exhibit intrinsic tyrosine kinase activity. Nevertheless, they stimulate different signaling pathways in cytoplasm of target cells, including those dependent on Src, a cytoplasmic tyrosine kinase. Steroid-induced Src activation regulates cell cycle progression, survival, migration, and associated processes, such as cell growth and differentiation. Androgen stimulation of human prostate cancer-derived LNCaP cells triggers cell cycle progression and proliferation. The key event in this process is the association of androgen receptor (AR) with Src. This association triggers activation of the Src/Ras/Erk pathway and finally impacts cell cycle. Androgen stimulation of fibroblasts also induces AR/Src association, which triggers DNA synthesis. Prevention of this association by a receptor-derived peptide competing for AR interaction with Src specifically inhibits the androgen receptor-dependent proliferative effect in vitro and in vivo.