Pten-loss Dysregulated Pathways in Prostate Cancer

前列腺癌中 Pten 丢失失调通路

• 批准号: 8259702
• 负责人: Zhenbang Chen
• 金额: $ 36.26万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259702
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Address; Adenocarcinoma; African American; Age-Months; Age-Years; American; Androgens; Award; Cancer Etiology; Castration; Caucasians; Caucasoid Race; Cell Aging; Cell Line; Cessation of life; Characteristics; Data; Employee Strikes; Ethnic group; Event; Genes; Goals; Growth; Human; In Vitro; Incidence; Knockout Mice; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Molecular; Morbidity - disease rate; Mus; Mutant Strains Mice; Mutate; Mutation; Oncogenic; PTEN gene; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphotransferases; Prostate; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Protein p53; Proto-Oncogene Proteins c-akt; Race; Recurrent tumor; Refractory; Regulation; Resistance; Role; Serine; Specificity; Stress; Testing; Transgenic Mice; Tumor Suppressor Genes; Up-Regulation; androgen independent prostate cancer; cancer health disparity; in vivo; insight; men; mortality; mouse model; novel; oncoprotein p21; overexpression; p19ARF; response; tumor progression; tumorigenesis

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.

前列腺癌中PTEN缺失调控通路的研究进展 摘要 前列腺癌是美国癌症相关死亡的第二大原因(仅次于肺癌) 与非裔美国人男性相比，非裔美国人男性前列腺癌的发病率和死亡率更高 高加索人。包括去势在内的前列腺癌发生和发展的分子机制 人们对耐药前列腺癌(CRPC)或雄激素不敏感前列腺癌(AI-PC)知之甚少。 PTEN和P53是人类多种癌症中最常见的两个缺失和/或突变基因 包括高级PCA。PTEN的缺失导致磷脂酰肌醇-3-羟基激酶的过度激活 (PI3K)和丝氨酸/苏氨酸激酶(Akt/PKB)。PTEN基因缺陷小鼠发育为高级别前列腺上皮内 肿瘤(HGPIN)和浸润性腺癌。我们最近在我们的小鼠模型中展示了 Pten的急性失活意外地引起了细胞衰老，这是一种新的抑制机制 癌症进展。癌基因和抑癌基因包括p19Arf、p53和p21的异常调节 在Pten缺陷小鼠的前列腺肿瘤中观察到了蛋白质。我们假设这一反常现象 P19Arf-P53通路的激活与Pten的丢失协同导致前列腺癌的进展。我们 建议检验这一假说，并研究Pten-p19Arf-P53调控的分子机制 利用小鼠模型和细胞系建立前列腺癌网络，目的如下：1.确定 P19Arf在前列腺癌进展中的作用2.确定p19Arf在细胞周期中的功能作用 Pten和P53在肿瘤发生过程中的串扰3.处理p19arf的后果和相关性 应用Pten/P53小鼠模型失活CRPC生长。从这个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作用的有价值的见解。