The role of 20‐HETE in the regulation of androgen receptor nuclear translocation

Abstract

Androgen has been shown to increase the synthesis of 20‐Hydroxyeicosatetraenoic acid (20‐HETE), a cytochrome P450 (CYP4A)‐arachidonate metabolite which in turn mediates cardiovascular effects of androgen including vascular dysfunction and hypertension. The mechanism underlying these interactions are unclear. We used LNCaP prostate cancer cell line the growth of which is androgen‐dependent. LNCaP cells produced high levels of 20‐HETE (290± 59 pg/mg) while in normal prostate epithelial cells 20‐HETE was undetectable. LNCaP cell growth was inhibited by HET0016, a selective CYP4A inhibitor, suggesting that 20‐HETE mediates the growth effect of androgen. Since androgen receptor (AR) nuclear translocation is critical for AR‐mediated growth and survival of prostate cancer, we examined whether 20‐HETE is involved in AR nuclear translocation. Treatment of LNCaP cells with 20‐HETE (100nM; 30min) showed a 2.5±0.48‐fold increase in nuclear AR levels. Since HSP90 is believed to tether AR in the cytoplasm towards a high affinity ligand binding conformation, we examined the effect of 20‐HETE on the HSP90‐AR association. 20‐HETE induced 2‐fold increase in cytoplasmic HSP90 association with AR. These results suggest that 20‐HETE, by increasing the association of HSP90 to AR, maintains AR in a high affinity ligand binding conformation and thereby increasing AR activation and translocation.