C-Jun and Androgen Signaling in Prostate Cancer Cells

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DESCRIPTION (provided by applicant): Androgens and the androgen receptor (AR) are involved in the growth and progression of prostate cancer. This makes prostate cancer initially sensitive to anti-androgen therapy. However, this sensitivity is lost when the cancer returns, which happens in virtually all patients. Interestingly, much evidence indicates that a functional AR and androgen regulated gene expression are still found in most hormone-independent prostate tumors. Androgen signaling in the prostate is dependent on AR and accessory factors. We have discovered that the proto-oncoprotein c-Jun is one such factor, acting as a mediator for androgen signaling in prostate cancer cells. Indeed, our preliminary evidence indicates that c-Jun acts as a coactivator for androgen-induced transcription, mediating the ligand-dependent dimerization and DNA binding of AR. This coactivation function of c-Jun is disrupted by c-Fos dimerization and does not depend on DNA binding by or Jun kinase (JNK) phosphorylation of c-Jun. These data clearly demonstrate that the c-Jun coactivation on androgen-regulated gene expression is functionally distinct from transactivation on AP-l-regulated gene expression. The major function of AR in the prostate appears to be regulating the proliferation and survival of prostate cells. Importantly, stable transfectants of LNCaP cells have been used to demonstrate that the c-Jun coactivation function is involved in androgen-dependent growth of these cells. Together, these data suggest that c-Jun has an important biological role on AR activity in prostate cancer cells. To test this hypothesis, the following specific aims are proposed: (1) to characterize the role of c-Jun on AR in androgen-dependent and androgen-independent growth of prostate cancer cells, (2) to study the effect of c-Jun coactivation on androgen-regulated gene expression in prostate cancer cells, and (3) to study the in vitro and in vivo physical interaction between AR and c-Jun. The importance of AR in the development and progression of prostate cancer is well established. Our discovery of c-Jun as a regulator of AR transcriptional activity and androgen-dependent proliferation of prostate cancer cells suggests a potential target for intervention of AR signaling. This may have relevance to both androgen-dependent and the more deadly androgenindependent prostate cancer.