Androgenic Inactivation of FOXO1 in Prostate Cancer

前列腺癌中 FOXO1 的雄激素失活

基本信息

批准号：
8069244
负责人：
DONALD J. TINDALL
金额：
$ 25.55万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8069244
关键词：
14-3-3 Proteins Ablation Affect Androgen Receptor Androgens Attenuated CDK2 gene CDK4 gene CDKN2A gene Cancer Etiology Cell Cycle Cell Proliferation Cell Survival Cells Cessation of life Clinic Cyclin-Dependent Kinase Inhibitor DNA Damage Data Diagnosis E2F Transcription Factor 1 EP300 gene FOXO1A gene Growth In Vitro Link Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Molecular Nuclear Export Oxidative Stress PTEN gene Phosphorylation Phosphorylation Inhibition Play Proliferating Cell Nuclear Antigen Prostate Proteins Radiation Radiation therapy Research Personnel Role Second Primary Cancers Serine Signal Transduction Testing Therapeutic Tumor Suppressor Proteins United States Withdrawal Work cancer cell chemotherapeutic agent effective therapy forkhead protein human CDK2 protein in vivo insight irradiation killings knock-down male programs tumor

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the second leading cause of cancer death in the United States. Cancer cells in the prostate depend on androgens for growth and survival. Mitogenic effects of androgens have been linked to their modulation of cell cycle regulatory molecules such as cyclin-dependent kinase 2 and 4 (CDK2 and CDK4). However, the molecular mechanisms for androgen-mediated cell survival are not fully elucidated. We and others have shown that androgens promote prostate cancer survival by antagonizing the function of PTEN, a tumor suppressor protein. Further studies have revealed that androgens block PTEN signaling by directly inhibiting the function of the forkhead transcription factor FOXO1 (FKHR), a key downstream target of PTEN. Our preliminary data demonstrate that CDK2 interacts with and phosphorylates FOXO1 in vitro and in vivo. CDK2 inhibits the function of FOXO1 through phosphorylation of serine 249. Importantly, CDK2- mediated phosphorylation and inhibition of FOXO1 can be reversed upon DNA damage induced by chemotherapeutic agents and irradiation. In view of the roles of androgen-mediated proliferation and survival and the anti-tumor effect of the interaction between androgen ablation and radiation therapy in the clinic, we hypothesize that CDK2-mediated inactivation of FOXO1 plays an important role in androgen-stimulated proliferation, survival, and oxidative stress in prostate cancer cells. To test this hypothesis, we propose to determine (1) whether CDK2-mediated phosphorylation of FOXO1 plays an essential role in androgen- stimulated proliferation and survival of prostate cancer cells; (2) whether androgen-induced phosphorylation of FOXO1 inhibits FOXO1 transcriptional activity in prostate cancer cells; (3) whether activation of FOXO1 is a key factor that mediates the synergistic anti-tumor effect of androgen ablation and radiation therapy. The findings from this work will provide new insights into the working mechanisms of androgen-induced proliferation and survival of prostate cancer cells. Moreover, they should enhance our understanding of the underlying mechanisms of the therapeutic advantage of androgen ablation and radiation therapy in the clinic.

描述（由申请人提供）：前列腺癌是美国癌症死亡的第二大原因。前列腺中的癌细胞依赖于雄激素的生长和生存。雄激素的有丝分裂作用与它们对细胞周期调节分子的调节有关，例如细胞周期蛋白依赖性激酶2和4（CDK2和CDK4）。但是，雄激素介导的细胞存活的分子机制尚未完全阐明。我们和其他人表明，雄激素通过拮抗肿瘤抑制蛋白PTEN的功能来促进前列腺癌的存活。进一步的研究表明，雄激素通过直接抑制PTEN的关键下游目标FOXO1（FKHR）的功能来阻止PTEN信号传导。我们的初步数据表明，CDK2在体外和体内与FOXO1相互作用并磷酸化。 CDK2通过丝氨酸249的磷酸化抑制FOXO1的功能。重要的是，CDK2介导的磷酸化和FOXO1的抑制作用可以在化学治疗剂和辐照的DNA损伤时反转。鉴于雄激素介导的增殖和生存的作用以及诊所中雄激素消融和放射治疗之间相互作用的抗肿瘤作用，我们假设CDK2介导的FOXO1的失活在雄激素刺激的增殖，生存胁迫，生存和氧化抗性细胞中起重要作用。为了检验这一假设，我们建议（1）CDK2介导的FOXO1的磷酸化是否在雄激素刺激的增殖和前列腺癌细胞的存活中起着至关重要的作用；（2）雄激素诱导的FOXO1是否抑制前列腺癌细胞中FOXO1转录活性；（3）FOXO1的激活是否是介导雄激素消融和放射治疗的协同抗肿瘤作用的关键因素。这项工作的发现将为雄激素诱导的前列腺癌细胞增殖和存活的工作机理提供新的见解。此外，它们应增强我们对诊所中雄激素消融和放射治疗的治疗优势的潜在机制的理解。