Role of Androgen Receptor in Bone Metastatic Prostate Cancer Apoptosis and NED

雄激素受体在骨转移性前列腺癌细胞凋亡和 NED 中的作用

• 批准号: 8685468
• 负责人: NIKKI A DELK
• 金额: $ 19.97万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685468
• 关键词: Ablation; Affect; Aftercare; Androgen Receptor; Androgens; Apoptosis; Apoptotic; Autophagocytosis; Bone Marrow; Cell Cycle; Cell Death; Cell Survival; Cells; Coculture Techniques; Disease; Disease Progression; Down-Regulation; Equilibrium; Growth; Homing; Hormones; Immune system; Life; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Microscopy; Modeling; Molecular; Molecular Biology; Neurosecretory Systems; Paracrine Communication; Process; Radiation; Radiation therapy; Recurrence; Relapse; Repression; Risk; Role; Stromal Cells; Western Blotting; Work; androgen independent prostate cancer; bone; bone cell; cancer cell; expression vector; prevent; programs; prostate cancer cell; public health relevance; receptor expression; response; therapeutic target; tool; tumor; tumor growth

DESCRIPTION (provided by applicant): Bone metastasis occurs in 80% of lethal androgen independent prostate cancer (PCa) cases, illustrating the need to better understand the mechanisms that regulate PCa growth in the bone. Bone cell paracrine signals affect cancer cell homing and adaption to growth in the bone. One likely means of PCa survival in bone is through the ability of cells to undergo neuroendocrine differentiation (NED). Neuroendocrine differentiated (NE) PCa cells are most prevalent in advanced PCa, correlate with androgen independent disease, and support disease progression. Furthermore, the NE PCa cells can de-differentiate and switch between dormant and proliferative states posing a risk for relapse after treatment. Non-dividing, long-lived NE PCa cells can evade conventional chemo-radiation therapy and contribute to tumor latency, yet remain primed for re-entry into the cell cycle to contribute to tumor growth during recurrence. Bone marrow stromal cell (BMSC) paracrine signaling induces apoptosis in co-cultured bone metastatic PCa cells. However, a subpopulation of the bone metastatic PCa cells can avoid apoptotic cell death and undergo NED. A working model is proposed in which upon arrival to the bone, metastatic PCa cells encounter a hostile microenvironment posed by the innate immune system present there that triggers PCa cell death in the majority of cells. A subpopulation of the PCa cells, however, can activate a molecular program that promotes PCa NED and cell survival in bone. Autophagy - a homeostatic, cell survival process - is up- regulated in PCa cells by BMSCs and helps maintain NE PCa cells in a trans-differentiated state. The molecular mechanisms that direct PCa cell fate either towards apoptosis or towards NED remain unclear. Understanding these mechanisms would provide an opportunity to intervene to prevent cells from undergoing NED and tip the balance toward apoptosis, greatly reducing the odds of relapse. This project aims to demonstrate that BMSCs promote either apoptosis or NED through a common mechanism that involves the repression of androgen receptor (AR) expression, and furthermore, show that autophagy is a cellular rheostat that determines whether a PCa cell undergoes apoptosis or NED following down regulation of AR expression. Using molecular biology tools such as microscopy, western blot, and expression vectors to characterize BMSC-induced PCa apoptosis and NED when AR expression and autophagy are modulated, the following specific aims are proposed: Specific Aim 1: Demonstrate that BMSC-mediated AR repression induces PCa apoptosis or PCa NED. Specific Aim 2: Determine if autophagy protects PCa cells from apoptosis and directs these cells towards NED in response to BMSC-induced AR repression. Specific Aim 3: Dissect the mechanism by which BMSC paracrine signaling represses PCa AR expression.

描述（由申请人提供）：骨转移发生在80％的致命雄激素独立前列腺癌（PCA）病例中，这说明了需要更好地了解调节骨骼PCA生长的机制。骨细胞旁分泌信号会影响癌细胞的托管并适应骨骼的生长。 PCA在骨中生存的一种可能手段是通过细胞经历神经内分泌分化（NED）的能力。神经内分泌分化（NE）PCA细胞在晚期PCA中最普遍，与雄激素独立疾病相关，并支持疾病进展。此外，NE PCA细胞可以在休眠状态和增生状态之间取消分化和切换，从而带来治疗后复发的风险。非分裂的长期NE PCA细胞可以逃避常规的化学放射治疗并导致肿瘤潜伏期，但仍可以重新进入细胞周期，以在复发过程中促进肿瘤生长。骨髓基质细胞（BMSC）旁分泌信号传导在共培养的骨转移性PCA细胞中诱导凋亡。但是，骨转移性PCA细胞的亚群可以避免凋亡细胞死亡并经历NED。提出了一个工作模型，在该模型中，到达骨骼后，转移性PCA细胞会遇到一种敌对的微环境，该环境由存在的先天免疫系统带来，该系统会触发大多数细胞中的PCA细胞死亡。但是，PCA细胞的亚群可以激活促进骨骼中PCA NED和细胞存活的分子程序。自噬 - 一种稳态的细胞存活过程 - 通过BMSC在PCA细胞中进行了调节，并有助于将NE PCA细胞保持在跨分化状态。将PCA细胞命运引导到凋亡或NED的分子机制尚不清楚。了解这些机制将提供一个干预的机会，以防止细胞进行NED并将平衡倾斜到凋亡，从而大大减少了复发的几率。该项目的目的是证明BMSC通过涉及抑制雄激素受体（AR）表达的共同机制促进凋亡或NED，然后表明自噬是一种细胞的损害，它决定了PCA细胞是否经过pCA细胞会受到细胞凋亡或降低AR表达调节后的NED。使用分子生物学工具，例如显微镜，蛋白质印迹和表达向量来表征BMSC诱导的PCA凋亡，而在调节AR表达和自噬时，提出了以下特定目的：具体目的1：证明BMSC介导的AR抑制作用诱导PCA凋亡或PCA NED。具体目标2：确定自噬是否保护PCA细胞免受凋亡的影响，并将这些细胞引导响应BMSC诱导的AR抑制作用。特定目标3：剖析BMSC旁分泌信号抑制PCA AR表达的机制。