RESUMEN
The oncogene DJ-1 has been associated with multiple cancers, including prostate cancer, where it can be stabilized by androgens and antiandrogens. However, little data exist on the expression pattern and function of DJ-1 in prostate cancer. To address the function of DJ-1 in prostate, a yeast two-hybrid screen was done to identify novel DJ-1 binding proteins. The androgen receptor (AR) was identified and confirmed as a DJ-1 binding partner. This is the first evidence that DJ-1 directly interacts with AR. We also show that modulation of DJ-1 expression regulated AR transcriptional activity. Importantly, both the subcellular localization of DJ-1 and the interaction with AR are regulated by androgens and antiandrogens. Additionally, immunohistochemical staining on two human prostate cancer tissue arrays was done providing the first large-scale expression analysis of DJ-1 in prostate. DJ-1 expression did not change with Gleason pattern but increased after androgen deprivation therapy, indicating that it may be involved in the development of androgen independence. These data provide a novel mechanism where DJ-1-mediated regulation of AR may promote the progression of prostate cancer to androgen independence.
Asunto(s)
Antagonistas de Andrógenos/farmacología , Antineoplásicos Hormonales/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias Hormono-Dependientes/metabolismo , Proteínas Oncogénicas/metabolismo , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Andrógenos/deficiencia , Núcleo Celular/metabolismo , Humanos , Masculino , Neoplasias Hormono-Dependientes/genética , Neoplasias Hormono-Dependientes/patología , Proteínas Oncogénicas/biosíntesis , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Unión Proteica , Proteína Desglicasa DJ-1 , Receptores Androgénicos/genética , Análisis de Matrices Tisulares , Transcripción GenéticaRESUMEN
BACKGROUND: Mechanisms regulating the transition from hormone responsive to hormone refractory prostate cancer (PCa) have remained unclear. METHODS: We analyzed androgen and anti-androgen treatment on endogenous AR activity in primary human prostate epithelial (HPE) cells cultured directly from patient radical prostatectomy specimens utilizing a transiently infected gene reporter (TIGR) assay. RESULTS: Flutamide treatment exhibited agonist activities in HPE cells derived from tumor and non-tumor specimens which contained wild-type AR. After proteomic comparison of these cells to those where flutamide functioned normally as an antagonist, we identified DJ-1, a positive regulator of AR. DJ-1 expression increased in HPE and LNCaP cells during flutamide treatment as a result of DJ-1 protein stabilization. CONCLUSION: Stabilization of AR and its co-regulators in the absence of androgen may partially account for anti-androgen withdrawal syndrome and potentially contribute to the development of hormone refractory PCa.
