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），与高加索人相比，非裔美国男性中PCa的发病率和死亡率甚至更高。导致前列腺癌（包括去势抵抗性前列腺癌（CRPC）或雄激素不敏感性前列腺癌（AI-PC））发生和进展的分子机制知之甚少。PTEN和p53是包括晚期PCa在内的多种人类癌症中最常缺失和/或突变的两种基因。PTEN的缺失导致磷脂酰肌醇-3-OH激酶（PI 3 K）和丝氨酸/Thr激酶（Akt/PKB）的过度活化。Pten缺陷小鼠发展为高级别前列腺上皮内瘤变（HGPIN）和侵袭性腺癌。我们最近在我们的小鼠模型中证明，Pten的急性失活意外地促进细胞衰老，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p19 Arf、p53和p21蛋白的异常调节。我们推测p19 Arf-p53通路的异常激活与Pten丢失协同作用导致前列腺癌进展。本研究拟利用小鼠前列腺癌模型和细胞系来验证这一假说，并探讨Pten-p19 Arf-p53网络在前列腺癌发生发展中的分子调控机制，具体目的如下：1）明确p19 Arf在前列腺癌发生发展中的作用。2)探讨p19 Arf在肿瘤发生过程中Pten和p53相互作用中的作用。3)使用Pten/p53小鼠模型探讨CRPC生长中p19 Arf失活的后果和相关性。从这个奖项获得的结果将为我们提供有价值的见解ARF在前列腺癌进展中的新作用。

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.