Androgen induces adaptation to oxidative stress in prostate cancer: Implications for treatment with radiation therapy

Radiation therapy is a standard treatment for prostate cancer (PC). The postulated mechanism of action for radiation therapy is the generation of reactive oxygen species (ROS). Adjuvant androgen deprivation (AD) therapy has been shown to confer a survival advantage over radiation alone in high-risk localized PC. However, the mechanism of this interaction is unclear. We hypothesize that androgens modify the radioresponsiveness of PC through the regulation of cellular oxidative homeostasis. Using androgen receptor (AR) ⁺ 22rv1 and AR^- PC3 human PC cell lines, we demonstrated that testosterone increased basal reactive oxygen species (bROS) levels, resulting in dose-dependent activation of phospho-p38 and pAKT, and increased expression of clusterin, catalase, and manganese superoxide dismutase. Similar data were obtained in three human PC xenografts; WISH-PC14, WISH-PC23, and CWR22, growing in testosterone-supplemented or castrated SCID mice. These effects were reversible through AD or through incubation with a reducing agent. Moreover, testosterone increased the activity of catalase, superoxide dismutases, and glutathione reductase. Consequently, AD significantly facilitated the response of AR⁺ cells to oxidative stress challenge. Thus, testosterone induces a preset cellular adaptation to radiation through the generation of elevated bROS, which is modified by AD. These findings provide a rational for combined hormonal and radiation therapy for localized PC.