Poster Sessions

CANCER-22

Dean Frohlich

D. Frohlich, M. Barber, J. Arnold

Role of Nrf2 in DHEA+ TGF Beta 1-induced Reactive Prostate Stromal Cells

Dehydroepiandrosterone (DHEA) is the most abundant endogenous adrenal steroid and declines markedly with aging. It is increasingly consumed as an over-the-counter dietary supplement for its purported anti-aging effects, yet its usefulness, long-term safety and effects on prostate tissues remain uncertain. Transforming growth factor beta-1 (TGFB1), a pro-inflammatory cytokine that participates in many cellular processes, such as proliferation and apoptosis, is overexpressed in reactive stroma and exerts multiple effects on carcinogenesis. Nrf2 is a transcription factor that has been demonstrated to mediate gene expression of detoxification enzymes through the antioxidant-response element in response to ROS, carcinogens, and xenobiotics. We have shown that DHEA metabolism is increased in reactive prostate stroma in the presence of TGFB1. While TGFB1 has been shown to inhibit Nrf2 expression, we investigated whether activation of Nrf2 could decrease TGFB1 induction of reactive stroma, potentially normalizing reactive stroma. Primary prostate stromal cells derived from radical prostatectomy tissue (6S) and normal prostate (PRSC) were treated with DHEA+/- TGFB1. Nrf2 was activated by treatment with tert-butylhydroquinone (tBHQ). Expression of Nrf2 regulated detoxification enzymes were analyzed by real-time PCR and Western blot. Combined administration of TGFB1 + DHEA decreased Nrf2-mediated gene expression of several detoxification enzymes, including NQO1, and HO-1. tBHQ treatment lead to increased gene expression of these enzymes, reversing the decrease induced by TGFB1 + DHEA in both 6S and PRSC cell cultures. In this model of reactive stroma in the prostate, TGFB1+DHEA decreased Nrf2-induced detoxification enzymes, whereas tBHQ reversed these effects. Additional natural products known to activate the Nrf2 pathway will be tested to determine effectiveness in normalizing reactive prostate stroma.