Skp2 in androgen-dependent proliferation of prostate cancer cells

描述（由申请人提供）：前列腺癌已成为西方人群中最常见的男性癌症。前列腺癌通常以雄激素依赖性（AD）形式开始，其可以用雄激素消融疗法有效治疗。然而，雄激素消融疗法几乎总是导致更积极的雄激素非依赖性（AI）形式的疾病。关于这一重要问题的大多数研究都集中在确定从AD到AI的疾病进展中的细胞和分子变化。在本申请中，我们建议将重点放在了解雄激素-雄激素受体（AR）如何发挥作用以促进AD前列腺癌细胞的增殖。雄激素-AR促进AD前列腺癌细胞的增殖和分化。我们相信，更好地了解雄激素-AR如何促进AD前列腺癌细胞的增殖，将有助于了解如何特异性靶向AR的增殖促进功能，这可能会导致AD前列腺癌的新治疗，而不会损害癌细胞分化。与雄激素消融治疗相比，这将建立治疗AD前列腺癌的新范例，雄激素消融治疗抑制AD前列腺癌细胞的增殖和分化。由于已经发现AR的功能对于至少一些雄激素非依赖性（AI）前列腺癌是重要的，因此靶向AR的增殖促进功能也将影响目前无法治愈的AI前列腺癌的治疗。我们在本申请中要测试的假设是，F-box蛋白Skp 2是AR在介导AD和一些AI前列腺癌细胞增殖中的重要下游效应物，而与它们的分化无关，并且特异性靶向Skp 2代表了治疗AD和一些AI前列腺癌的新概念。在具体目标1中，我们将确定AR调节Skp 2的分子机制。在具体目标2中，我们将确定雄激素对人AD前列腺癌异种移植物中Skp 2的调节，并确定和比较去势和Skp 2敲低对异种移植物肿瘤生长和复发的影响。最后，在具体目标3中，我们将使用小鼠模型来确定Skp 2在由致癌水平的AR诱导的前列腺上皮增殖和转化中的作用，AR是人类前列腺癌的疑似原因。 公共卫生相关性：前列腺癌已成为西方人群中最常见的男性癌症。前列腺癌的一个基本特性是其最初的雄激素依赖性和不可避免的进展到致命的雄激素非依赖性形式的疾病。本项目旨在了解雄激素受体如何促进前列腺癌，并制定针对前列腺癌的治疗策略。

DESCRIPTION (provided by applicant): Prostate cancer has become the most common male cancer diagnosed in Western populations. Prostate cancer generally starts in an androgen-dependent (AD) form, which can be effectively treated with androgen ablation therapies. Androgen ablation therapies however almost always lead to more aggressive androgen-independent (AI) forms of the disease. Most research on this important issue has focused on identifying cellular and molecular changes in disease progression from AD to AI. In this application, we propose instead to focus on understanding how androgen-androgen receptor (AR) functions to promote proliferation of AD prostate cancer cells. Androgen-AR promotes both proliferation and differentiation of AD prostate cancer cells. We believe that a better understanding of how androgen-AR promotes proliferation of AD prostate cancer cells will shed light on how to specifically target the proliferation-promoting function of AR, which may lead to new treatment for AD prostate cancer that does not compromise cancer cell differentiation. This will establish a new paradigm of treating AD prostate cancer as compared to androgen ablation therapy, which inhibits both proliferation and differentiation of AD prostate cancer cells. Since functions of AR have been found important for at least some androgen-independent (AI) prostate cancer, targeting the proliferation-promoting functions of AR will impact on the treatment of AI prostate cancer as well, which is current incurable. Our hypothesis to be tested in this application is that the F-box protein Skp2 is an important downstream effector of AR in mediating proliferation of AD and some AI prostate cancer cells independently of their differentiation, and specifically targeting Skp2 represents a new concept in treatment of AD and some AI prostate cancer. In Specific Aim 1, we will determine the molecular mechanisms underlying the regulation of Skp2 by AR. In Specific Aim 2, we will determine the regulation of Skp2 by androgen in human AD prostate cancer xenografts and determine and compare the effects of castration and Skp2 knockdown on xenograft tumor growth and recurrence. Finally in Specific Aim 3, we will use mouse models to determine the role of Skp2 in prostate epithelium proliferation and transformation induced by oncogenic levels of AR, which is a suspected cause of prostate cancer in humans. PUBLIC HEALTH RELEVANCE: Prostate cancer has become the most common male cancer diagnosed in Western populations. A fundamental property of prostate cancer is its initial androgen-dependence and inevitable progression to lethal androgen-independent forms of the disease. This project aims to understand how the androgen receptor promotes prostate cancer and to develop targeted treatment strategy for prostate cancer.