Continuous AhR Activity Accelerates Prostate Cancer Progression in African American Men
Technical Report,01 Jul 2017,30 Jun 2018
Clark Atlanta University Atlanta United States
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Recent studies demonstrate that, for men with clinically localized, non-metastatic high-risk prostate cancer receiving long-term androgen deprivation therapy ADT and dose-escalated radiotherapy RT, a pre-RT prostate specific antigen PSA value greater than 0.5 ngml after ADT predicts for decreased time to distant metastases and a decrease in overall survival. In these studies, AA men were significantly associated with failure to achieve a pre-RT PSA value less than 0.5 ngml. These elevated PSA levels are a direct result of sustained androgen receptor signaling despite ADT. AA men would benefit greatly from more potent anti-androgenic therapies in combination with radiation. The objective of this proposal is to compare the level and effect of AhR activity in AA and CA prostate cancer cells and tissues. We hypothesize that constitutive AhR signaling is responsible for the sustained androgen receptor signaling seen in CRPC and that AA men have elevated AhR activity compared to CA men. Western blot analysis revealed that AA prostate cancer cell lines have increased AhR expression and nuclear localization compared to the CA counterparts. In addition, inhibition of AhR activity reduces biological properties not affected by inhibition of androgen receptor with antagonist casodex. AhR specific inhibitor decreased the growth rate, migration and invasion of androgen-insensitive prostate cancer cell lines. The level of inhibition achieved correlates to the level of constitutive AhR activity. Identification of this unknown mechanism for prostate cancer progression will provide a novel therapeutic target to reduce aggressiveness of castration resistant prostate cancer that is not achieved by current therapies and could directly address the health disparity associated with PCa. Previous studies have not considered the existence of constitutive AhR signaling in prostate cancer or its ability to promote prostate cancer progression.
- Medicine and Medical Research