| The growth of prostate cancer during its early stages is androgen dependent. Thus, androgen ablation therapy and antiandrogens are widely used for the treatment of prostate cancer. Several regimens are currently used for the reduction of serum androgen levels, including treatments luteinizing hormone-releasing hormone (LHRH) analogues and the blockade of AR transcriptional activity by antiandrogens such as flutamide. Some patients develop “antiandrogen withdrawal syndrome (AWS)”, wherein discontinuation of antiandrogen therapy actually stops prostate cancer growth and reduces the secretion of prostate-specific antigen (PSA), suggesting that certain hormonal therapies may acquire some agnostic properties to promote prostate cancer progression through unclear signaling pathways. This intriguing phenomenon has prompted us to study the mechanisms that may contribute to the failure of hormonal therapy. Here we report that the antiandrogen flutamide can increase the activation of mitogen-activated protein kinases (MAPK) in prostate cancer cells through the EGFR-dependent pathway. This observation suggests that, in addition to antagonizing AR function, flutamide may induce proliferative signals. This study provides a novel explanation for the side effects of flutamide on prostate cancer proliferation.; Members of a subgroup of the nuclear receptor superfamily, the nuclear orphan receptors, have been identified through sequence similarity to known nuclear hormone receptors, although their physiological ligands are still unidentified. Testicular receptor 4 (TR4), a member of this subgroup, was cloned from prostate and testis cDNA libraries. Here we demonstrate that TR4 can bind to the DR1-HRE of the hepatitis B virus (HBV) core promoter and suppress the core promoter activity through direct interaction with a liver-enriched nuclear receptor, HNF4α, which is essential for the transcriptional initiation of HBV replication. Furthermore, TR4 can serve as a bridging factor though which AR regulates the HBV core promoter, which contains no consensus androgen response element (ARE) sequences. Our study provides evidence that nuclear receptors such as TR4 and AR act as repressors of the HBV core promoter, which will guide our further characterization of their in vivo functions in HBV replication and virus associated liver pathogenesis using AR or TR4 knock-out mouse models. |
