| Redox-sensitive transcription factor AP-1 complex such as c-Jun and c-Fos are historically associated with cellular growth and transformation. A unique member of the AP-1 complex, JunD, has been shown to inhibit cell proliferation, promote differentiation, and mediate stress responses. We previously reported that LNCaP human prostate carcinoma cells exposed to growth inhibitory concentrations of androgen (i.e. 1--10 nM R1881) exhibit increased reactive oxygen species levels (ROS), increased JunD/AP-1 DNA binding and transactivation, and other markers of oxidative stress. These effects are attenuated by the co-administration of the antiandrogen bicalutamide. LNCaP cells transiently overexpressing JunD exhibit ROS-induced growth inhibition, comparable to the changes in growth and ROS levels observed upon androgen exposure. LNCaP cells stably overexpressing a transcriptionally inactive form of JunD, JunDDeltaTA, were unable to respond to androgen-induced changes in growth and ROS levels. However, LNCaP cells with stable siRNA-mediated silencing of JunD expression (≥75%) exhibited a slower growth rate and higher ROS levels, compared to controls. Upon exposure to 0.001--10 nM R1881, JunD-silenced LNCaP cells displayed decreased sensitivity to androgen-induced growth inhibition and ROS levels. Altogether, we show that JunD is necessary and sufficient to modulate androgen-induced growth inhibition in LNCaP cells. We also demonstrate that androgen-induced growth inhibition promotes a pro-oxidant redox state in LNCaP cells via JunD expression and activity. Moreover, we provide evidence to suggest that JunD may have a dual function in promoting and protecting LNCaP cells from growth-related oxidative stress via the androgen receptor signaling axis. Understanding the mechanism of androgen-mediated changes in the growth and redox status of prostate carcinoma cells is of central importance to our efforts for preventing and treating prostate cancer initiation and progression. |
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