Pten-loss Dysregulated Pathways in Prostate Cancer

描述（由申请人提供）：前列腺癌（PCa）是美国男性癌症相关死亡的第二大原因（仅次于肺癌），非裔美国男性前列腺癌的发病率和死亡率甚至高于白种人。导致去势抵抗性前列腺癌（CRPC）或雄激素不敏感性前列腺癌（AI-PC）等前列腺癌发生和发展的分子机制尚不清楚。PTEN和p53是包括晚期PCa在内的多种人类癌症中最常缺失和/或突变的两个基因。PTEN的缺失导致磷脂酰肌醇-3- oh激酶（PI3K）和丝氨酸/苏氨酸激酶（Akt/PKB）的过度活化。pten缺陷小鼠发生高级别前列腺上皮内瘤变（HGPIN）和浸润性腺癌。我们最近在小鼠模型中证明，Pten的急性失活意外地引发细胞衰老，这是一种抑制癌症进展的新机制。在pten缺陷小鼠的前列腺肿瘤中观察到癌基因和肿瘤抑制因子包括p19Arf、p53和p21蛋白的异常调控。我们假设p19Arf-p53通路的异常激活与Pten的缺失共同导致前列腺癌的进展。我们拟通过小鼠模型和细胞系验证这一假设，研究Pten-p19Arf-p53网络在前列腺癌中的调控分子机制，具体目的如下：1)明确p19Arf在前列腺癌进展中的作用。2)确定p19Arf在肿瘤发生过程中Pten和p53串扰中的功能作用。3)利用Pten/p53小鼠模型研究p19Arf失活对CRPC生长的影响及其相关性。该奖项的结果将为我们了解ARF在前列腺癌进展中的新作用提供有价值的见解。

DESCRIPTION (provided by the applicant): 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.