MAOA and AR Reciprocal Crosstalk in Prostate Cancer

项目摘要/摘要 前列腺癌(PC)是美国男性最常见的非皮肤癌，一生发病率为七分之一， 也是导致美国男性癌症死亡的第二大原因。雄激素受体(AR)是最主要的 PC生长、存活和进展的致癌驱动因素。AR定向治疗目前是主要的治疗方法 治疗方案。尽管最初的应答率超过90%，但PC最终复发并进展为 致命的去势抵抗PC(CRPC)，AR信号的重新激活发生在低雄激素环境中。 最近推出FDA批准的下一代抗雄激素，包括苯扎鲁胺(ENZ)和 阿比特龙(ABI)改善了CRPC的治疗格局，但出现耐药 仍然几乎是普遍的，没有AR靶向的治疗选择。这些令人沮丧的事实强调了 临床迫切需要确定新的分子靶点并开发有效的治疗方法来对抗 先进的PC。通过对公开可用的临床PC数据集进行集成分析，并结合功能 在对AR阳性PC细胞的研究中，我们提出了单胺氧化酶A(MAOA)，它与AR协同作用 推广PC，作为CRPC中AR靶向治疗的理想候选方案。我们确定了一个 在PC细胞中MAOA和AR之间新的相互作用。雄激素诱导MAOA的表达 相反，MAOA沉默通过降低AR靶基因而显著降低AR活性 雄激素充盈和耗竭条件下PC细胞对雄激素刺激的表达和反应性 在CRPC异种移植模型中也是如此。我们发现MAOA和MAOA有显著的共表达 包括CRPC在内的多个临床数据集中的AR靶基因(PSA、TMPRSS2、NKX3.1)。重要的是，我们 在CRPC数据集的样本中发现MAOA基因组扩增和/或表观遗传激活， 在我们的CRPC患者队列中，MAOA蛋白的表达增加了。此外，我们还演示了 通过遗传或药理学方法抑制MAOA可增强其生长抑制作用 雄激素敏感、CR和抗雄激素抵抗的PC细胞中的ENZ和ABI。根据这些调查结果，我们将 验证MAOA通过相互串扰和下游收敛与AR协同的假设 发出信号，充分发挥MAOA/AR效应，促进AR驱动的PC生长和进展，并共同靶向 MAOA/AR是治疗CRPC和逆转抗雄激素耐药的一种可行、有效的策略。至 针对这一假设，本文提出了三个目标。在目标1中，我们将阐明MAOA的机制基础- PC细胞内AR的相互作用。在目标2中，我们将描述MAOA在调节 CRPC在异种移植模型中的发展和进展。在目标3中，我们将确定MAOA的疗效 治疗慢性前列腺癌和逆转体内外对下一代抗雄激素耐药性的抑制剂。 这些研究将为CRPC的AR监管提供基本的创新见解，并指明一条道路 为开发治疗晚期PC的新的联合疗法。

Project Summary/Abstract Prostate cancer (PC) is the most common non-skin cancer in American men, with a lifetime incidence of 1 in 7, and also the second leading cause of cancer death in American men. Androgen receptor (AR) is the primary oncogenic driver of PC growth, survival and progression. AR-directed therapy is currently the principal treatment regimen. Despite initial response rates exceeding 90%, PC eventually relapses and progresses to fatal castration-resistant PC (CRPC), where reactivation of AR signaling occurs in a low-androgen environment. Recent introduction of FDA-approved next-generation antiandrogens, including enzalutamide (ENZ) and abiraterone acetate (ABI), have improved the CRPC treatment landscape, but emergence of drug resistance remains nearly universal, with no AR-targeted therapeutic options afterwards. These dismal facts underscore the pressing clinical need to identify new molecular targets and develop effective therapies to combat advanced PC. Through integrated analysis of publicly available clinical PC data sets coupled with functional studies in AR-positive PC cells, we propose monoamine oxidase A (MAOA), which synergizes with AR to promote PC, as an ideal therapeutic candidate to complement AR-targeted therapy in CRPC. We identified a novel reciprocal interaction between MAOA and AR in PC cells. MAOA expression is induced by androgen treatment; and conversely, MAOA silencing significantly reduces AR activity by lowering AR target gene expression and responsiveness to androgen stimulation in PC cells under both androgen-replete and depleted conditions as well as in a CRPC xenograft model. We showed significant positive co-expression of MAOA and AR target genes (PSA, TMPRSS2, NKX3.1) in multiple clinical data sets, including CRPC. Importantly, we found MAOA genomic amplification and/or epigenetic activation in 64% of samples in a CRPC data set, reinforced by elevated MAOA protein expression in our CRPC patient cohort. Additionally, we demonstrated that inhibition of MAOA by genetic or pharmacological approaches enhanced the growth-inhibiting effects of ENZ and ABI in androgen-sensitive, CR and antiandrogen-resistant PC cells. Based on these findings, we will test the hypothesis that MAOA synergizes with AR through reciprocal crosstalk and convergent downstream signaling to amply MAOA/AR effects promoting AR-driven PC growth and progression, and that co-targeting MAOA/AR is an actionable, effective strategy to treat CRPC and reverse antiandrogen drug resistance. To address this hypothesis, three aims are proposed. In Aim 1, we will elucidate the mechanistic basis of MAOA- AR reciprocal interaction in PC cells. In Aim 2, we will characterize the role of MAOA in regulating the development and progression of CRPC in xenograft models. In Aim 3, we will determine the efficacy of MAOA inhibitors for treating CRPC and reversing resistance to next-generation antiandrogens in vitro and in vivo. These studies will provide fundamental innovative insights into AR regulation in CRPC and illuminate a path toward the development of new combination therapy for advanced PC.