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，持续的慢性炎症在前列腺癌发生中是重要的。在前列腺组织活检和根治性前列腺切除术标本中经常观察到的慢性炎性病变是衰老过程的结果，也是前列腺癌发展的前兆。这些发现得到了长期使用抗氧化剂可降低前列腺癌风险的报告的支持。FOX家族成员“O”控制着影响细胞增殖、炎症、修复DNA损伤和氧化剂/抗氧化剂平衡的重要基因网络。在缺乏生长信号的情况下，FOXO家族成员在细胞核中保持转录活性。在通过PI 3 K-Akt途径刺激后，FOXO蛋白被磷酸化并易位至细胞质，从而废除其转录活性。我们最近已经证明（在2008年美国癌症研究协会年会的最新会议上提交，并作为提案中的初步数据）FOXO蛋白在人前列腺癌细胞系和组织中的细胞区室中的失调和再分布。此外，FOXO 3A的水平显着高于细胞核的细胞质部分作为年龄和疾病进展的函数。与20-28周龄的非转基因同窝出生小鼠相比，Akt的超活化导致Foxo 3a与14-3-3的结合增加及其在TRAMP小鼠前列腺细胞质中的积累。这降低的Foxo 3a水平与TRAMP小鼠前列腺中p21/WAF 1、MnSOD和Cu/ZnSOD的基础水平的下调相关，从而将氧化剂/抗氧化剂平衡向增加的氧化应激和癌症进展转移。基于这些有趣的发现，我们建议FOXO信号通路作为一个关键的分子靶点，为预防前列腺癌的发展战略。本提案利用这些新发现，旨在通过靶向FOXO信号通路来研究芹菜素（一种常见水果和蔬菜中存在的植物类黄酮）的癌症预防潜力。本提案将采用TRAMP模型，这是一种合适的动物模型，以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对人类前列腺癌有影响。

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.