Roles of Nemo-like kinase in CaP and its effects on androgen receptor signaling

描述(由申请人提供)：MAPK调节细胞的生长、分化和应激反应，许多关键的信号通路受到Mark信号的交叉调节。以前的研究已经证明了Mark通路和雄激素受体(AR)信号之间存在串扰，雄激素受体(AR)信号在正常前列腺癌和前列腺癌的生长控制中发挥着关键作用。我们已经证明，MAPK样蛋白Nemo样激酶(NLK)在前列腺癌进展过程中的表达发生变化，NLK显著抑制AR介导的信号转导，并最终刺激CAP细胞的凋亡。本项目的目的是阐明NLK对前列腺细胞AR信号转导的作用机制，并评估其作为新的治疗靶点的前景。我们将对NLK与AR的相互作用进行机制研究，包括转录分析和蛋白质水平的修饰，以及辅助因子的关联。我们还将研究NLK对前列腺细胞的促凋亡作用及其与AR信号抑制的关系，并使用我们先进的动物模型研究NLK的体内效应。深入了解NLK在前列腺癌进展中的作用、AR转录调控及其生物学效应，将有助于认识重建CAP中功能性NLK信号的价值，并为前列腺癌的治疗干预指明新的模式。本研究旨在阐明NLK诱导CAP细胞凋亡的本质和机制，以及NLK在这些细胞中的表达对关键信号通路的影响。具体目标： 1)探讨NLK的表达与前列腺癌临床参数的关系。 2)探讨NLK对AR导向转录的影响机制。 3)探讨NLK促进CAP细胞凋亡的机制。 4)探讨NLK在体内对前列腺癌肿瘤生长的影响。 健康相关性：晚期前列腺癌是一种毁灭性的、致命的、几乎无法治愈的疾病。通过研究NEMO样激酶甚至可以杀死对其他疗法具有抵抗力的前列腺癌细胞的能力，我们希望为晚期前列腺癌的新的、有前途的治疗方法指明方向。

DESCRIPTION (provided by applicant): The MAPKs regulate cell growth, differentiation, and stress responses, and many critical signaling pathways are subject to cross-regulation by MARK signaling. Previous studies have yielded evidence of crosstalk between the MARK pathways and androgen receptor (AR) signaling, which plays a critical role in growth control of both normal prostate and prostate cancer. We have shown that the MAPK-like protein, Nemo-like kinase (NLK) expression is altered during prostate cancer progression, and that NLK dramatically inhibits AR-mediated signaling and ultimately stimulating apoptosis in CaP cells. The goal of this project is to elucidate the mechanisms of NLK effects on AR signaling in prostate cells and to evaluate its promise as a new therapeutic target. We will perform mechanistic studies on interaction of NLK with AR, including transcriptional analysis and protein-level modifications, and cofactors associations. We will also investigate the proapoptotic effects of NLK in prostate cells and its relation to inhibition of AR signaling, and study in vivo effects of NLK using our advanced animal models. A deeper understanding of the NLK roles in prostate cancer progression and regulation of AR-directed transcription and its biological effects will lead to an appreciation of the value of reconstituting functional NLK signaling in CaP and point the way to new modes of therapeutic intervention in this disease. The specific aims of this proposal are intended to elucidate the nature and mechanisms of induction of apoptosis in CaP cells by NLK and characterize the effects of NLK expression on critical signaling pathways in these cells. Specific aims: 1) To investigate associations of NLK expression with clinical parameters of prostate cancer. 2) To investigate the mechanisms of NLK effects on AR-directed transcription. 3) To investigate the mechanisms whereby NLK promotes apoptosis of CaP cells. 4) To investigate the effects of NLK expression on prostate cancer tumors in vivo. Health relevance: Advanced prostate cancer is a devastating, fatal, and almost untreatable disease. By studying the ability of nemo-like kinase to kill even prostate-cancer cells that are resistant to other treatments, we hope to point the way to new and promising therapeutic approaches for advanced prostate cancer.