C-Jun and Androgen Signaling in Prostate Cancer Cells

描述（由申请人提供）：雄激素和雄激素受体（AR）参与前列腺癌的生长和进展。这使得前列腺癌最初对抗雄激素治疗敏感。然而，当癌症复发时，这种敏感性就会丧失，这几乎发生在所有患者身上。有趣的是，许多证据表明，功能性AR和雄激素调控的基因表达仍然存在于大多数非依赖性前列腺肿瘤中。前列腺中的雄激素信号传导依赖于AR和辅助因子。我们已经发现，原癌蛋白c-Jun就是这样一个因子，在前列腺癌细胞中充当雄激素信号传导的介体。事实上，我们的初步证据表明，c-Jun作为雄激素诱导的转录的共激活因子，介导AR的配体依赖性二聚化和DNA结合。c-Jun的这种共激活功能被c-Fos二聚化破坏，并且不依赖于c-Jun的DNA结合或Jun激酶（JNK）磷酸化。AR在前列腺中的主要功能似乎是调节前列腺细胞的增殖和存活。重要的是，LNCaP细胞的稳定转染子已被用于证明c-Jun共激活功能参与这些细胞的雄激素依赖性生长。总之，这些数据表明c-Jun对前列腺癌细胞中的AR活性具有重要的生物学作用。为了检验这一假设，提出了以下具体目标：（1）表征c-Jun在前列腺癌细胞的雄激素依赖性和雄激素非依赖性生长中对AR的作用，（2）研究c-Jun共激活对前列腺癌细胞中雄激素调节的基因表达的影响，（3）研究AR与c-Jun在体内外的物理相互作用。我们发现c-Jun作为AR转录活性和前列腺癌细胞雄激素依赖性增殖的调节剂，这表明了AR信号转导干预的潜在靶点。这可能与雄激素依赖性和更致命的雄激素非依赖性前列腺癌有关。

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.