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Figure 2. Signaling via AR occurs by both ligand-dependent and ligand-independent mechanisms. The male steroid hormones, androgen and testosterone (T) are produced by the testes and adrenal glands and manifest their endocrine effects on PCa cells via ligand-dependent activation of AR signaling (left). Inside the PCa cells, T is converted to a highly potent analog dihydrotestosterone (DHT) by the 5α-reductase enzyme. DHT binding to AR releases it from its chaperone, the heat shock proteins (Hsp). The activated AR then dimerizes and translocates to the nucleus, where it recruits coregulators of transcription to increase PCa growth. Ligand-independent activation of AR (right) can also occur due to multiple signaling pathways, primarily activated by inflammatory cytokines, and utilize ROS as second messengers. Therefore, amplified redox signaling networks can facilitate non-AR signaling, resulting in CRPC outgrowth post hormone deprivation. AR: androgen receptor; PCa: prostate cancer; ROS: reactive oxygen species; CRPC: castrate resistant prostate cancer