Mechanisms of castration resistance in prostate cancer (PCa). Reproduced with permission from the Massachusetts Medical Society . During androgen-dependent progression, PCa cells depend primarily on the androgen receptor (AR) for growth and survival. When the AR is inactive, it is bound to heat shock proteins (HSP) in the cytoplasm of prostate cells. The androgen dihydrotestosterone (DHT) binds to the AR, dissociating it from HSPs. The DHT-bound AR translocates into the nucleus, dimerizes, and binds to the androgen-response elements, thereby activating genes involved in cell growth. During androgen-independent progression, PCa relies on various cellular pathways, some involving the AR and others bypassing it. In the former type of pathway, a mutated AR may be activated by various ligands. In addition, deregulated growth factors and cytokines can activate the AR, usually with the help of AR coactivators. The AR may be amplified and therefore activated by reduced levels of DHT. In the pathways that bypass the AR, the loss of PTEN reverses the inhibition of the phosphatidylinositol 3-kinase/Akt pathway, permitting activated Akt to phosphorylate Bad. This activation results in the release of Bcl2, which eventually leads to cell survival. In addition, androgen-independent cells may overexpress Bcl2. PCa cells may develop neuroendocrinelike behaviour. Neuroendocrine cells secrete neuropeptides that induce the growth of adjacent cells, and thus PCa may survive therapeutic interventions.