AR signal mediators in prostate cancer

雄激素受体(AR)介导的雄激素信号在控制细胞增殖和分化中起着关键作用 在前列腺癌的发生和发展中起重要作用。AR是一种激素调节的转录因子，调节 动态基因表达程序。然而，在正常情况下，AR的功能是如何从其促分化改变的 前列腺癌中前列腺上皮细胞促增殖和肿瘤生长的机制还知之甚少。通过功能 基因组学，我们发现了一种新的核ATPase辅助调节蛋白，它在物理和功能上都 与AR和其他关键细胞信号调节器。值得注意的是，这种辅助调节因子是由雄激素诱导的雄激素依赖性 癌细胞，在雄激素非依赖性细胞和肿瘤中高表达并可能被放大。我们的 初步研究还表明，它通过特异性地介导促增殖和 前列腺癌细胞的生存信号通路，同时抑制雄激素诱导的 差异化计划。综上所述，我们假设这个协同调节因子是特定AR功能的关键调节因子 在AR的致瘤信号中通过其二元性开关机制，其异常功能代表一个 前列腺癌向激素抵抗状态转化的重要机制。为了检验我们的假设，我们 建议确定其在前列腺癌细胞周期进程、细胞存活和侵袭中的作用，并确定其特异性 这个AR协同调节因子整合的信号通路。为了在生理相关的环境中检查它的功能，我们 将决定它的异常功能如何影响肿瘤的生长和进展到激素剥夺治疗抵抗 状态。拟议研究的完成将为AR介导的分子基础提供新的见解 前列腺癌中的致癌信号，并导致治疗该疾病的新的治疗策略。

Androgen signaling through androgen receptor (AR) plays a pivotal role in control of cell proliferation and differentiation in the development and progression of prostate cancer. AR, a hormone regulated transcription factor, regulates dynamic gene expression programs. However, how the function of AR is altered from its pro-differentiation in normal prostate epithelium to pro-proliferation and tumor growth in prostate cancer is poorly understood. Through functional genomics, we have uncovered a novel nuclear ATPase coregulator protein that physically and functionally associates with AR and other key cell signaling regulators. Strikingly, this coregulator is induced by androgen in androgendependent cancer cells, highly expressed and possibly amplified in androgen-independent cells and tumors. Our preliminary studies also reveal that it plays very unique functions by specifically mediating the pro-proliferation and survival signaling pathways in prostate cancer cells and, at the same time, suppressing the androgen-induced differentiation program. Taking together, we hypothesize that this coregulator is a key mediator of specific AR function in AR’s tumorigenic signaling through its dualistic switch mechanism and that its aberrant function represents an important mechanism of the conversion of prostate cancer to the hormone-refractory state. To test our hypothesis, we propose to establish its role in prostate cancer cell cycle progression, cell survival and invasion and define the specific signaling pathways integrated by this AR coregulator. To examine its function in a physiologically relevant setting, we will determine how its aberrant function affects tumor growth and progression to hormone deprivation therapy resistant status. The completion of the proposed study will provide new insights into the molecular underpinnings of AR-mediated tumorigenic signaling in prostate cancer and lead to a novel therapeutic strategy in treatment of the disease.