Castration and antiandrogens have been used to prevent prostate cancer growth at all stages. However, androgen withdrawal by chemical or surgical castration only slows tumor progression as prostate cancer eventually becomes hormone-independent, resumes growth and kills the patient. This suggests other growth factors are involved in the process. TGF-beta is one of few classes of endogenous inhibitors of cell growth. Loss of responsiveness to TGF-beta is believed to be a major factor in tumor formation. In prostate cancer, the TGF-beta pathway is often inactive with loss expression of TGF-beta receptor. In our preliminary studies, we find that: 1) Smad7, a TGF-beta antagonist, directly interacts with androgen receptor (AR) and inhibits AR-induced gene transcription. Importantly, Smad7 was immunocoprecipitated with histone deacetylase (HDAC), indicating its potential role as a transcription repressor. 2) Smad6, the other antagonist, interacts with Tip6O and RIP 140 androgen receptor coactivators and also inhibits AR-mediated gene expression. Our findings suggest the interaction between antagonist Smads and AR/coactivators serve as a novel cross-talk mechanism between TGF-beta and androgen, since expression of Smad7 and Smad6 are turned on by TGF-beta signaling. In prostate cancers, defect TGF-beta signaling results in deficiency of both Smad7 and Smad6, which may in turn shut down the antagonist Smads capability in down-regulating AR-enhanced gene expression and prostate cell proliferation. Therefore, we hypothesize that the interaction of antagonist Smads with AR and its coactivators such as RIP 140, regulates AR transcription activity and inhibits AR-induced prostate cell growth. Characterization of the cross-talk mechanisms will be helpful in understanding TGF-beta mediated inhibition of prostate cancer growth. We will pursue the following specific aims:1) Characterize the interactions of Smad7 with AR and Smad6 with an AR coactivator, RIP140. 2) Examine function of Smad7and Smad6 on androgen-induced cellular response. 3) Determine the molecular mechanism underlying Smad7 and Smad6 induced alternation of AR activity. 4) Characterize the effects Smad7 and smad6 on prostate cancer progression in nude mice. We believe that characterization of the cross-talk mechanism between TGF-beta and androgen would enable development of a TGF-beta based therapeutic strategy for the treatment of prostate cancer and improve anti-androgen treatment for prostate patients.
NIH ExPorter
NIH ExPorter