FOXO: A Target for Prostate Cancer Prevention

FOXO：预防前列腺癌的目标

基本信息

批准号：
7750415
负责人：
Sanjeev Shukla
金额：
$ 7.85万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-16 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7750415
关键词：
Adenocarcinoma Adhesions Affect Age Aging Aging-Related Process American Association of Cancer Research American Cancer Society Angiogenic Factor Animal Model Antioxidants Apigenin Apoptosis Benign Benign Prostatic Hypertrophy Binding Biopsy Boxing Cancer Etiology Cancer Model Cell Cycle Cell Cycle Arrest Cell Nucleus Cell Proliferation Cells Cessation of life Chemopreventive Agent Chronic Clinical Cytoplasm DNA DNA Damage DNA Repair Data Development Diagnosis Disease Progression Down-Regulation EP300 gene Epidemiologic Studies Equilibrium Event FOXO3A gene Family Family member Flavonoids Free Radicals Gene Expression Generations Genes Genetic Genetic Transcription Goals Growth Growth Factor Human Immune Immunoprecipitation Incidence Individual Inflammation Inflammatory Inflammatory Response Laboratory Study Lateral Lesion Link Longevity MLLT7 gene Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of prostate Masks Mitotic Cell Cycle Modeling Molecular Chaperones Molecular Target Mus Neoplastic Cell Transformation Nuclear Nuclear Localization Signal Nude Mice Oxidants Oxidative Stress PC3 cell line PTGS2 gene Pathogenesis Pathway interactions Phosphorylation Phosphotransferases Plants Play Prevention strategy Preventive Prostate Prostate carcinoma Prostatic Diseases Proteins Publishing Radical Prostatectomy Regulation Reporting Risk Risk Factors Role Signal Pathway Signal Transduction Specimen Staging Stimulus Testing Tissues Transcription Coactivator Transgenic Organisms Tumor Tissue United States Validation Vascularization Work Xenograft Model age related base carcinogenesis cell growth chemokine cyclin-dependent kinase inhibitor 1B cytokine design forkhead protein fruits and vegetables in vivo interest meetings member men novel oncoprotein p21 prevent programs prostate cancer prevention prostate carcinogenesis transcription factor tumor tumor growth tumor progression upstream kinase

项目摘要

DESCRIPTION (provided by applicant): Epidemiological studies and clinical observations suggest that persistent chronic inflammation is important in prostate carcinogenesis. The chronic inflammatory lesions frequently observed in prostate tissue biopsies and radical prostatectomy specimens are consequence to the aging process and precursor to prostate cancer development. These findings are supported by the reports that long-term use of anti-oxidant decreases the risk of prostate cancer. Members of the FOX family group 'O' control important network of genes that influence cell proliferation, inflammation, repair DNA damage, and oxidants/antioxidants balance. In the absence of growth signal, the FOXO family members remain transcriptionally active in the nucleus. Upon stimulus via PI3K-Akt pathway, FOXO proteins are phosphorylated and translocates to the cytoplasm, abrogating its transcriptional activity. We have recently demonstrated (Submitted in the Late- Breaking Session at the Annual Meeting of American Association for Cancer Research, 2008 and as preliminary data in the proposal) deregulation and redistribution of FOXO proteins in the cellular compartments in human prostate cancer cell lines and tissues. Furthermore, levels of FOXO3A were significantly higher in the cytosolic fraction than the nucleus as a function of age and disease progression. Hyperactivation of Akt causes increased Foxo3a binding with 14-3-3 and its accumulation in the cytoplasm of TRAMP mice prostates, compared to non-transgenic littermates at 20-28 weeks of age. This decreased Foxo3a levels correlated with downregulation of the basal levels of p21/WAF1, MnSOD and Cu/ZnSOD in the prostates of TRAMP mice thereby shifting the oxidants/antioxidants balance towards increased oxidative stress and cancer progression. Based on these interesting findings we suggest FOXO signaling pathway as a key molecular target for the development of preventive strategies against prostate cancer. The present proposal capitalizes on these novel findings and is designed to investigate the cancer preventive potential of apigenin, a plant flavonoid present in common fruits and vegetables, by targeting FOXO signaling pathway. This proposal will employ TRAMP model which is an appropriate animal model to test our working hypothesis as it mimics progressive forms of human prostatic disease. Validation of this hypothesis may have implications for prostate cancer in humans.

描述（由申请人提供）：流行病学研究和临床观察表明，持续的慢性炎症在前列腺癌发生中很重要。在前列腺组织活检中经常观察到的慢性炎性病变和前列腺切除术的根治性病变是衰老过程和前列腺癌发展前体的结果。这些发现得到了报道，即长期使用抗氧化剂会降低前列腺癌的风险。 FOX家族组的成员“ O”控制重要的基因网络，这些网络会影响细胞增殖，炎症，修复DNA损伤以及氧化剂/抗氧化剂平衡。在没有生长信号的情况下，FOXO家族成员在细胞核中保持转录活性。通过PI3K-AKT途径刺激后，FOXO蛋白被磷酸化并易位到细胞质，从而消除了其转录活性。我们最近证明了（在2008年美国癌症研究协会年度会议上，在提案中作为初步数据提交了），在人类前列腺癌细胞系和组织中，FOXO蛋白在细胞室中放松管制和重新分布。此外，胞质分数的FOXO3A水平显着高于核的年龄和疾病进展的函数。与在20-28周龄时的非转基因同窝仔相比，AKT的过度激活与14-3-3的结合增加了FOXO3A的结合及其在流浪小鼠前列腺细胞质中的积累。这种降低的FOXO3A水平与流浪小鼠前列腺中P21/WAF1，MNSOD和CU/ZnSOD的基础水平的下调相关，从而改变了氧化剂/抗氧化剂在增加氧化应激和癌症进展方面的平衡。根据这些有趣的发现，我们建议FOXO信号通路是针对前列腺癌的预防策略开发的关键分子靶标。目前的提案利用了这些新颖的发现，旨在通过靶向FOXO信号通路来研究一种普通水果和蔬菜中植物类黄酮的癌症预防潜力。该提案将采用流浪汉模型，这是一个适当的动物模型，可以测试我们的工作假设，因为它模仿了人类前列腺疾病的渐进形式。对该假设的验证可能对人类的前列腺癌有影响。