Oxidative Stress and Antiandrogen Resistance in Prostate Cancer

Abstract

Antiandrogen (AA) resistance in prostate cancer (PCa) prevents successful hormonal therapy. Aberrant activity of the androgen receptor (AR) and oxidative stress (OS) may contribute to this resistance; AR signaling induces ROS and NADPH Oxidases (NOX) correlate with PCa aggressiveness. Peroxiredoxin‐1 (Prx‐1) is an OS induced, antioxidant response element (ARE) regulated gene. Prx‐1 enhances AR transactivation, which may limit AA efficacy. AREs are regulated by two transcription factors, Nrf1 and Nrf2. ARE genes were implicated in resistance in tamoxifen resistant MCF‐7 cells. We used 4 cell lines representing 4 subsequent stages of PCa progression (RWPE1, RWPE2, LNCaP, and C42B) to establish a correlation between AA resistance and ARE gene expression. We used RT‐PCR, western, and cell viability assays to determine how levels of Prx‐1, Nrf1, Nrf2, NOX4, and NOX5 expression correlate with bicalutamide resistance. With increasing aggressiveness and resistance, enhanced expression of Prx‐1, Nrf1, NOX4, and NOX5 was observed, while decreasing expression of Nrf2 was seen. Interestingly, bicalutamide treatment also increased Nrf1 protein expression in LNCaP and C42B cells. Our results have shown a direct correlation between expression and/or activity of ARE proteins and antiandrogen resistance. Understanding these mechanisms of AA resistance may aid in developing new treatments for aggressive PCa.