Pten-loss Dysregulated Pathways in Prostate Cancer

描述(申请人提供)：前列腺癌(PCA)是美国男性癌症相关死亡(仅次于肺癌)的第二大原因，非裔美国男性的发病率和死亡率比高加索男性更高。导致前列腺癌发生和发展的分子机制，包括去势抵抗型前列腺癌(CRPC)或雄激素不敏感前列腺癌(AI-PC)，目前尚不清楚。PTEN和P53是包括晚期前列腺癌在内的多种人类肿瘤中最常见的两个缺失和/或突变基因。PTEN的缺失导致磷脂酰肌醇-3-羟基激酶(PI3K)和丝氨酸/苏氨酸激酶(Akt/PKB)的过度激活。PTEN基因缺陷小鼠发生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了Pten的急性失活意外地引起了细胞衰老，这是一种抑制癌症进展的新机制。在Pten基因缺陷小鼠的前列腺癌中观察到癌基因和抑癌基因包括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缺失协同导致前列腺癌的进展。我们建议利用小鼠模型和细胞系来验证这一假说，并研究Pten-p19Arf-p53网络在前列腺癌中的调控分子机制，目的如下：1)明确p19Arf在前列腺癌进展中的作用。2)探讨p19Arf在Pten和P53相互作用中的作用。3)利用Pten/P53小鼠模型研究p19Arf失活在CRPC生长中的作用及相关性。从这一奖项中获得的结果将为我们提供对ARF在前列腺癌进展中的新角色的有价值的见解。

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.