Targeting the Androgen Receptor by Taxol in Castration-Resistant Prostate Cancer.

Both cell culture and clinical studies show that the androgen receptor (AR) plays a key role in the growth and survival of castration-resistant prostate cancer (CRPC), a lethal form of the disease in the clinic, suggesting that AR remains to be a major target for the treatment of CRPC. Taxol chemotherapy is one of the few therapeutic options for patients with CRPC albeit the underlying mechanism is not fully understood. We have demonstrated recently that Taxol (paclitaxel and its semisynthetic analogue docetaxel) treatment of 22Rv1, a CRPC cell line that expresses the tumor suppressor gene PTEN, inhibits AR transcriptional activity. In contrast, paclitaxel failed to inhibit AR activity in the PTEN-deficient C4-2 CRPC cells. Docetaxel treatment of 22Rv1 xenografts in mice induced mitotic arrest and a decrease in expression of the AR target gene prostate-specific antigen (PSA) mainly in tumor cells adjacent to vascular vessels. Further studies demonstrated that Taxol inhibition of the AR is mediated, at least in part, by Taxol-induced nuclear accumulation of FOXO1, a key downstream effector protein of PTEN and increased association of FOXO1 with the AR. These studies suggest that the status of the functional PTEN/FOXO pathway and the drug bioavailability may be the two key determinants for Taxol chemoresistance of CRPC in the clinic.