FOXO: A Target for Prostate Cancer Prevention

描述(由申请人提供)： 流行病学研究和临床观察表明，持续性慢性炎症在前列腺癌的发生中起重要作用。前列腺组织活检和前列腺癌根治术标本中常见的慢性炎性病变是衰老过程的结果，也是前列腺癌发展的先兆。这些发现得到了长期使用抗氧化剂降低前列腺癌风险的报告的支持。福克斯家族‘O’的成员控制着重要的基因网络，这些基因影响细胞增殖、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家族成员在细胞核内保持转录活性。在PI3K-Akt途径的刺激下，FOXO蛋白被磷酸化并转移到细胞质中，使其转录活性丧失。我们最近展示了(在2008年美国癌症研究协会年会上提交的，作为提案中的初步数据)FOXO蛋白在人类前列腺癌细胞系和组织中的细胞间隔室中的解除调控和重新分布。此外，随着年龄和疾病进展，胞浆中FOXO3a的水平显著高于细胞核。与20-28周龄的非转基因小鼠相比，Akt的过度激活导致Foxo3a与14-3-3结合增加，并在TRAMP小鼠前列腺细胞质中积聚。这降低了Foxo3a水平，这与TRAMP小鼠前列腺中p21/WAF1、MnSOD和Cu/ZnSOD的基础水平下调有关，从而使氧化剂/抗氧化剂的平衡转向氧化应激增加和癌症进展。基于这些有趣的发现，我们建议FOXO信号通路作为前列腺癌预防策略发展的关键分子靶点。本提案利用这些新的发现，旨在通过靶向FOXO信号通路来研究芹菜素的癌症预防潜力。芹菜素是一种存在于常见水果和蔬菜中的植物黄酮类化合物。这项建议将采用TRAMP模型，这是一个合适的动物模型来测试我们的工作假设，因为它模拟了人类前列腺疾病的进行性形式。这一假设的验证可能会对人类前列腺癌产生影响。

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.