Pten-loss Dysregulated Pathways in Prostate Cancer

前列腺癌中Pten丢失的失调通路 总结 前列腺癌（PCa）是美国癌症相关死亡的第二大原因（仅次于肺癌） 男性中，非裔美国男性中PCa的发病率和死亡率甚至更高， 白种人导致前列腺癌发生和发展的分子机制，包括去势 对耐药前列腺癌（CRPC）或雄激素不敏感前列腺癌（AI-PC）的了解很少。 PTEN和p53是多种人类癌症中最常见的两种缺失和/或突变基因 包括先进的PCa PTEN缺失导致磷脂酰肌醇-3-OH激酶过度活化 （PI 3 K）和丝氨酸/Thr激酶（Akt/PKB）。pten缺陷小鼠发生高度前列腺上皮内病变 肿瘤（HGPIN）和浸润性腺癌。我们最近在小鼠模型中证明， Pten急性失活出乎意料地促进细胞衰老，这是一种新的抑制细胞衰老的机制， 癌症进展癌基因和抑癌基因包括p19 Arf、p53和p21的异常调节 在Pten-缺陷小鼠的前列腺肿瘤中观察到蛋白质。我们假设 p19 Arf-p53途径的激活与Pten丢失协同作用导致前列腺癌进展。我们 因此，我们拟验证这一假设，并研究Pten-p19 Arf-p53调控的分子机制 使用小鼠模型和细胞系在前列腺癌中的网络，具有以下特定目的：1.以限定 p19 Arf在前列腺癌进展中的作用2.为了确定p19 Arf在细胞凋亡中的功能作用， 肿瘤发生过程中Pten和p53的相互作用。3.为了解决p19 Arf的后果和相关性， 使用Pten/p53小鼠模型在CRPC生长中的失活。从这个奖项中获得的结果将为我们提供 ARF在前列腺癌进展中的新作用的有价值的见解。

Pten-loss Dysregulated Pathways in Prostate Cancer Summary Prostate Cancer (PCa) is the second leading cause of cancer-related deaths (after lung cancer) in American men, and the morbidity and the mortality to PCa are even higher in African American men as compared Caucasians. Molecular mechanisms leading to the initiation and progression of PCa including castration resistant prostate cancer (CRPC) or androgen insensitive prostate cancer (AI-PC) are poorly understood. PTEN and p53 are the two most frequently deleted and/ or mutated genes in a variety of human cancers including advanced PCa. Loss of PTEN leads to the hyperactivation of phosphatidylinositol-3-OH kinase (PI3K) and serine/Thr kinase (Akt/PKB). Pten-deficient mice develop high grade prostatic intraepithelial neoplasia (HGPIN) and invasive adenocarcinoma. We have recently demonstrated in our mouse model that the acute inactivation of Pten unexpectedly elicits cellular senescence, a novel mechanism suppressing cancer progression. Aberrant regulation of oncogenes and tumor suppressors including p19Arf, p53 and p21 proteins have been observed in prostate tumors of Pten-deficient mice. We HYPOTHESIZE that aberrant activation of p19Arf-p53 pathways cooperates with Pten loss to result in prostate cancer progression. We propose to test this hypothesis and to study the molecular mechanisms of regulating Pten-p19Arf-p53 network in prostate cancer using mouse models and cell lines with following Specific Aims: 1. to define the role of p19Arf in prostate cancer progression. 2. to determine the functional roles of p19Arf in the crosstalk of Pten and p53 during tumorigenesis. 3. to address the consequence and relevance of p19Arf inactivation in CRPC growth using Pten/p53 mouse model. Results obtained from this award will provide us valuable insights into novel roles of ARF in prostate cancer progression.